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136 results on '"MESH : Mutation"'

1. Regulation of Orange Carotenoid Protein Activity in Cyanobacterial Photoprotection

Author: Céline Bourcier de Carbon, Diana Kirilovsky, Léa Comolet, Adjélé Wilson, Adrien Thurotte, Fugui Xiao, Rocío López-Igual, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Laboratory of Biophysics, Wageningen University and Research Centre [Wageningen] ( WUR ), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Wageningen University and Research [Wageningen] (WUR)
Subjects: Models, Molecular, 0106 biological sciences, Cyanobacteria, MESH : Escherichia coli, Light, Physiology, [SDV]Life Sciences [q-bio], MESH : Synechocystis, MESH : Models, Biological, Plant Science, Orange (colour), MESH: Synechocystis, 01 natural sciences, polycyclic compounds, Phycobilisomes, MESH : Bacterial Proteins, MESH : Light, MESH: Bacterial Proteins, Carotenoid, chemistry.chemical_classification, 0303 health sciences, MESH: Escherichia coli, Synechocystis, food and beverages, MESH : Protein Binding, Articles, Fluorescence, Biofysica, Biochemistry, MESH : Mutation, MESH: Models, Molecular, Protein Binding, MESH : Fluorescence, MESH: Mutation, MESH : Models, Molecular, Biophysics, macromolecular substances, Biology, Models, Biological, 03 medical and health sciences, Bacterial Proteins, Escherichia coli, Genetics, Life Science, MESH: Protein Binding, MESH: Phycobilisomes, 030304 developmental biology, [ SDV ] Life Sciences [q-bio], Orange carotenoid protein, organic chemicals, MESH: Fluorescence, MESH: Models, Biological, biology.organism_classification, MESH: Light, MESH : Phycobilisomes, chemistry, Photoprotection, Mutation, bacteria, Phycobilisome, Excess energy, 010606 plant biology & botany
Abstract: International audience; Plants, algae, and cyanobacteria have developed mechanisms to decrease the energy arriving at reaction centers to protect themselves from high irradiance. In cyanobacteria, the photoactive Orange Carotenoid Protein (OCP) and the Fluorescence Recovery Protein are essential elements in this mechanism. Absorption of strong blue-green light by the OCP induces carotenoid and protein conformational changes converting the orange (inactive) OCP into a red (active) OCP. Only the red orange carotenoid protein (OCP(r)) is able to bind to phycobilisomes, the cyanobacterial antenna, and to quench excess energy. In this work, we have constructed and characterized several OCP mutants and focused on the role of the OCP N-terminal arm in photoactivation and excitation energy dissipation. The N-terminal arm largely stabilizes the closed orange OCP structure by interacting with its C-terminal domain. This avoids photoactivation at low irradiance. In addition, it slows the OCP detachment from phycobilisomes by hindering fluorescence recovery protein interaction with bound OCP(r). This maintains thermal dissipation of excess energy for a longer time. Pro-22, at the beginning of the N-terminal arm, has a key role in the correct positioning of the arm in OCP(r), enabling strong OCP binding to phycobilisomes, but is not essential for photoactivation. Our results also show that the opening of the OCP during photoactivation is caused by the movement of the C-terminal domain with respect to the N-terminal domain and the N-terminal arm.
Published: 2015
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2. High phosphatidylinositol 4-phosphate (PI4P)-dependent ATPase activity for the Drs2p-Cdc50p flippase after removal of its N- and C-terminal extensions

Author: Philippe Champeil, Pierre Le Maréchal, Joseph A. Lyons, Poul Nissen, José Luis Vázquez-Ibar, Cédric Montigny, Aurore Jacquot, Thibaud Dieudonné, Jakob Ulstrup, Miriam-Rose Ash, Guillaume Lenoir, Hassina Azouaoui, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Nordic-EMBL Partnership for Molecular Medicine, and PUMPkin (DANDRITE), Centre for Membrane Pumps in Cells and Disease (PUMPKIN), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut des Neurosciences de Paris-Saclay ( Neuro-PSI ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Nordic-EMBL Partnership for Molecular Medicine, and PUMPkin ( DANDRITE ), and Centre for Membrane Pumps in Cells and Disease ( PUMPKIN )
Subjects: 0301 basic medicine, Phosphatidylinositol 4-phosphate, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Saccharomyces cerevisiae, Plasma protein binding, Biochemistry, MESH: Thrombin, chemistry.chemical_compound, MESH : Phosphorylation, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 0302 clinical medicine, Adenosine Triphosphate, MESH: Saccharomyces cerevisiae Proteins, Phosphatidylinositol Phosphates, ATP hydrolysis, MESH : Arginine, lipid-protein interaction, MESH: Adenosine Triphosphate, MESH : Adenosine Triphosphate, Phospholipid Transfer Proteins, Phosphorylation, Phospholipids, MESH : Phospholipid Transfer Proteins, medicine.diagnostic_test, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Hydrolysis, Autophosphorylation, MESH: Phospholipid Transfer Proteins, Thrombin, MESH: Arginine, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH : Protein Binding, Phosphatidylserine, MESH: Phosphatidylinositol Phosphates, MESH: Saccharomyces cerevisiae, phosphoinositide, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, inhibition mechanism, MESH: Protein Domains, autophosphorylation, MESH : Mutation, MESH: Hydrolysis, Protein Binding, CDC50 protein, phosphatidylserine, Saccharomyces cerevisiae Proteins, MESH : Proteolysis, MESH: Mutation, Proteolysis, MESH : Calcium-Transporting ATPases, MESH: Proteolysis, Calcium-Transporting ATPases, Saccharomyces cerevisiae, Biology, Arginine, MESH : Phospholipids, MESH: Calcium-Transporting ATPases, MESH : Saccharomyces cerevisiae Proteins, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, 03 medical and health sciences, Protein Domains, MESH : Hydrolysis, Membrane Biology, medicine, Journal Article, MESH : Phosphatidylinositol Phosphates, MESH: Protein Binding, Phosphatidylinositol, Molecular Biology, MESH: Phospholipids, MESH: Phosphorylation, MESH : Protein Domains, MESH : Thrombin, Cell Biology, Flippase, flippase, 030104 developmental biology, chemistry, Mutation, 030217 neurology & neurosurgery, limited proteolysis
Abstract: International audience; P4-ATPases, also known as phospholipid flippases, are responsible for creating and maintaining transbilayer lipid asymmetry in eukaryotic cell membranes. Here, we use limited proteolysis to investigate the role of the N and C termini in ATP hydrolysis and auto-inhibition of the yeast flippase Drs2p-Cdc50p. We show that limited proteolysis of the detergent-solubilized and purified yeast flippase may result in more than 1 order of magnitude increase of its ATPase activity, which remains dependent on phosphatidylinositol 4-phosphate (PI4P), a regulator of this lipid flippase, and specific to a phosphatidylserine substrate. Using thrombin as the protease, Cdc50p remains intact and in complex with Drs2p, which is cleaved at two positions, namely after Arg104 and after Arg 1290, resulting in a homogeneous sample lacking 104 and 65 residues from its N and C termini, respectively. Removal of the 1291-1302-amino acid region of the C-terminal extension is critical for relieving the auto-inhibition of full-length Drs2p, whereas the 1-104 N-terminal residues have an additional but more modest significance for activity. The present results therefore reveal that trimming off appropriate regions of the terminal extensions of Drs2p can greatly increase its ATPase activity in the presence of PI4P and demonstrate that relief of such auto-inhibition remains compatible with subsequent regulation by PI4P. These experiments suggest that activation of the Drs2p-Cdc50p flippase follows a multistep mechanism, with preliminary release of a number of constraints, possibly through the binding of regulatory proteins in the trans-Golgi network, followed by full activation by PI4P.
Published: 2017
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3. Variability of tropism and replicative capacity of two naturally occurring influenza A H9N2 viruses in cell cultures from different tissues

Author: Wafa Tombari, Imen Elbehi, F. Amouna, Abdeljelil Ghram, Laboratoire d’Epidémiologie et de Microbiologie Vétérinaire ( LR11IPT03 ), Institut Pasteur de Tunis, and Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP )
Subjects: low pathogenicity influenza virus, 0301 basic medicine, viruses, medicine.medical_treatment, Cell, Amino Acid Motifs, Hemagglutinin Glycoproteins, Influenza Virus, Chick Embryo, Virus Replication, Food Animals, MESH : Chick Embryo, Influenza A Virus, H9N2 Subtype, MESH : Female, MESH : Neuraminidase, MESH : Influenza A Virus, H9N2 Subtype, Cells, Cultured, virus diseases, Trypsin, MESH : Specific Pathogen-Free Organisms, MESH : Influenza in Birds, Specific Pathogen-Free Organisms, MESH : Virus Replication, Titer, medicine.anatomical_structure, virus host range, MESH : Chickens, Female, MESH : Mutation, medicine.drug, MESH : Amino Acid Motifs, Neuraminidase, Culture cells, Biology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Tropism, Virus, Microbiology, Birds, 03 medical and health sciences, MESH : Amino Acid Substitution, MESH : Cells, Cultured, medicine, Animals, MESH : Birds, Protease, cell tropism, [ SDV ] Life Sciences [q-bio], General Immunology and Microbiology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Tropism, Virology, Reverse genetics, MESH : Hemagglutinin Glycoproteins, Influenza Virus, 030104 developmental biology, Viral replication, Amino Acid Substitution, Influenza in Birds, Mutation, Animal Science and Zoology, kinetic replication, MESH : Animals, Chickens
Abstract: International audience; Studies carried out on cell permissivity are of great interest to understand virus replication and pathogenicity. We described the results of a comparative analysis of replication efficiency of two naturally occurring influenza A H9N2 variants isolated from poultry and wild birds, differing by only two substitutions Q226L and T384N, in the receptor-binding site of haemagglutinin and the 380 loop region of NA proteins, respectively. Considering the overall growth of both viruses, lung cultures ensured the most efficient growth of TUN12L226N384 strain with titres up to 10(9) TCID50/ml whereas small intestine culture was highly susceptible to the TUN51Q226T384 virus reaching a titre of 10(6) TCID50/ml. The lowest replication was shown in liver cells. The addition of trypsin was essential for the replication of either virus in primary fibroblasts, but it had a marginal positive effect on virus replication in the four other culture types with maximum titres of 10(8) TCID50/ml. This means that in chicken, the proteolytic activation of the H9N2 viruses with the cleavage motif RSSR may be mediated by other endoproteases than trypsin. Further investigations should concentrate on the production of the appropriate set of viruses by a reverse genetics approach and the examination of cellular protease expression in chicken tissues. This would lead to a more complete understanding of the tropism of low-pathogenic Influenza A viruses.
Published: 2016
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4. Oncogenic Alterations in Papillary Thyroid Cancers of Young Patients

Author: G. Sassolas, Z. Hafdi Nejjari, A. Ferraro, M. S. Gandhi, C. Kwon Jung, E. Borbone, M. Decaussin Petrucci, B. Rousset, F. Borson Chazot, N. Berger, FUSCO, ALFREDO, registre rhone-alpin du cancer de la thyroide, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-registre rhone-alpins du cancer de la thyroide, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), departement de pathologie, Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -registre rhone-alpins du cancer de la thyroide, Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), G., Sassola, Z., Hafdi Nejjari, A., Ferraro, M. S., Gandhi, C., Kwon Jung, E., Borbone, M., Decaussin Petrucci, B., Rousset, F., Borson Chazot, N., Berger, and Fusco, Alfredo
Subjects: Male, Oncology, Pathology, Oncogene Proteins, Fusion, endocrine system diseases, MESH: Carcinoma, Papillary, Endocrinology, Diabetes and Metabolism, Disease, MESH : Oncogene Proteins, Fusion, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Endocrinology, MESH : Child, MESH: Child, MESH : Female, Young adult, Child, Lymph node, education.field_of_study, MESH : Prognosis, MESH : Genes, ras, Thyroid, Age Factors, Protein-Tyrosine Kinases, MESH : Adult, Prognosis, 3. Good health, medicine.anatomical_structure, Thyroid Cancer, Papillary, MESH: Thyroid Neoplasms, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, Mitogen-Activated Protein Kinases, MESH : Mutation, Adult, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH : Male, Population, MESH : Young Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030209 endocrinology & metabolism, MESH: Protein-Tyrosine Kinases, MESH: Prognosis, MESH : Carcinoma, Papillary, Thyroid carcinoma, Young Adult, 03 medical and health sciences, Median follow-up, MESH : Adolescent, Internal medicine, MESH : Protein-Tyrosine Kinases, medicine, Humans, Thyroid Neoplasms, education, MESH : Proto-Oncogene Proteins B-raf, MESH: Adolescent, MESH: Age Factors, MESH: Proto-Oncogene Proteins B-raf, MESH: Humans, business.industry, Carcinoma, MESH : Humans, MESH : Mitogen-Activated Protein Kinases, MESH: Adult, MESH: Mitogen-Activated Protein Kinases, Carcinoma, Papillary, MESH : Thyroid Neoplasms, MESH: Male, MESH: Genes, ras, Genes, ras, Mutation, MESH : Age Factors, business, MESH: Female, V600E, MESH: Oncogene Proteins, Fusion
Abstract: International audience; BACKGROUND: Papillary thyroid carcinoma (PTC) in young people usually has an aggressive initial presentation, though a good general prognosis despite recurrences in 10%-20% of patients. A number of genetic alterations that activate the mitogen-activated protein kinase (MAPK) pathway have been found in PTC. Some of these alterations have been identified as prognostic factors of PTC in adults. The objective of the current study was to comprehensively characterize all known oncogenic alterations of the MAPK pathway in young people. METHODS: One hundred three PTCs removed from 9 children, 19 adolescents, and 75 young adults were submitted to molecular analyses. RESULTS: Altogether, 57 alterations were found in 56 PTCs (55%) corresponding to V600E BRAF in 20.3%, RAS mutations in 12.6%, RET/PTC 1 in 11.6%, RET/PTC 3 in 8.7%, and rearrangement of NTRK in 1.9%. The prevalence of all alterations increased with age (22.2% in children; 52.6% in adolescents, 51.4% in adults 20-25 years, and 55.1% in adults 25-35 years). Prevalence increased from 39.2% earlier to 61.3% after 20 years mainly due to BRAF mutations. Classic-type PTC was associated with a larger prevalence of alterations, predominantly BRAF and RET/PTC, whereas the follicular variant was chiefly associated with RAS. RET/PTC (1 and 3) was significantly associated with extrathyroid extension (ET) and lymph node metastasis (es) (LNM). This association was found in the adult group. There were no associations of BRAF or RAS mutations with ET or LNM. A 3-year median follow up was available for 90 patients. RET/PTC 1 and 3 was associated with short-term disease dissemination (cervical lymph node recurrences and distant metastases) in young adults (p=0.001). Persistent illness was more prevalent in patients with (15%) than in patients without (7%) genetic alterations. CONCLUSION: PTCs in young patients display a low prevalence of the already identified oncogenic alterations. The increasing prevalence with age is mainly due to V600E BRAF mutation. There is no relation between tumor aggressiveness and BRAF mutation. There is a relation between the presence of RET/PTC (1 and 3) and the histological and clinical short-term aggressiveness of PTC in the population of young adults. Such a relation is not found in children and adolescents.
Published: 2012
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5. Are pathogenic bacteria just looking for food? Metabolism and microbial pathogenesis

Author: Didier Hocquet, Laurence Rohmer, Samuel I. Miller, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Laboratoire Chrono-environnement ( LCE ), and Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC )
Subjects: MESH : Virulence Factors, Microbial metabolism, MESH : Urease, medicine.disease_cause, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH : Biological Evolution, MESH: Animals, MESH: Metabolomics, MESH : Host-Pathogen Interactions, Pathogen, MESH : Intestines, 2. Zero hunger, Genetics, 0303 health sciences, Biological Evolution, Urease, Intestines, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Multigene Family, Host-Pathogen Interactions, MESH : Mutation, MESH: N-Acetylneuraminic Acid, MESH: Intestines, Microbiology (medical), MESH: Mutation, MESH : Gene Transfer, Horizontal, Gene Transfer, Horizontal, Virulence Factors, MESH: Urease, MESH : Multigene Family, Virulence, MESH : Metabolomics, MESH: Biological Evolution, Biology, Microbiology, Article, 03 medical and health sciences, Metabolomics, Virology, medicine, Animals, Humans, MESH : Bacteria, Loss function, MESH: Virulence Factors, 030304 developmental biology, MESH: Humans, Bacteria, 030306 microbiology, Host (biology), MESH : Humans, MESH: Host-Pathogen Interactions, Pathogenic bacteria, biology.organism_classification, N-Acetylneuraminic Acid, MESH: Gene Transfer, Horizontal, MESH: Bacteria, Mutation, MESH: Multigene Family, MESH : Animals, MESH : N-Acetylneuraminic Acid
Abstract: It is interesting to speculate that the evolutionary drive of microbes to develop pathogenic characteristics was to access the nutrient resources that animals provided. Environments in animals that pathogens colonize have also driven the evolution of new bacterial characteristics to maximize these new nutritional opportunities. This review focuses on genomic and functional aspects of pathogen metabolism that allow efficient utilization of nutrient resources provided by animals. Similar to genes encoding specific virulence traits, some genes encoding metabolic functions have been horizontally acquired by pathogens to provide a selective advantage in host tissues. Selective advantage in host tissues can also be gained in some circumstances by loss of function due to mutations that alter metabolic capabilities. Greater understanding of bacterial metabolism within host tissues should be important for increased understanding of host-pathogen interactions and the development of future therapeutic strategies.
Published: 2011
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6. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. : Activating STAT3 mutations in hepatocellular adenoma

Author: Jeanne Tran Van Nhieu, Michel Bihl, Karine Poussin, Mohamed Amessou, Paulette Bioulac-Sage, Jessica Zucman-Rossi, Charles Balabaud, Camilla Pilati, Jean-Charles Nault, Tina Izard, Valérie Paradis, Gabrielle Couchy, Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Labex Immuno-oncology, Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Pathologie [Clichy], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Department of Cancer Biology, The Scripps Research Institute, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and This work was supported by the association pour la recherche Contre le Cancer (ARC, grant n°3194), Inserm (Réseaux de recherche clinique et réseaux de recherche en santé des populations), Collection Nationale des Carcinomes Hépatocellulaires, the Ligue Nationale Contre le Cancer ('Cartes d'identité des tumeurs' program) and the BioIntelligence collaborative program. C.P., M.A. and J-C.N. are supported by a fellowship from the MENRT, Inca and ARC, respectively. T.I. is supported by the National Institutes of Health grants GM071596, AI055894, and AI067949.
Subjects: MESH : Tyrosine, Male, Models, Molecular, MESH : Liver Neoplasms, MESH : Mutant Proteins, MESH : Aged, MESH : RNA, Small Interfering, SH2 domain, medicine.disease_cause, HNF1A, STAT3, MESH : Phosphorylation, 0302 clinical medicine, MESH : STAT3 Transcription Factor, Cytokine Receptor gp130, Immunology and Allergy, CTNNB1, MESH : Female, SOCS3, Phosphorylation, RNA, Small Interfering, 0303 health sciences, Mutation, Liver Neoplasms, DNA, Neoplasm, MESH : Adult, Middle Aged, SAA, 3. Good health, MESH : Cytokine Receptor gp130, JAK1, src-Family Kinases, JAK2, MESH : Dimerization, 030220 oncology & carcinogenesis, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Female, MESH : DNA, Neoplasm, MESH : Mutation, CRP, IL6ST, Dimerization, Tyrosine kinase, Src, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src, MESH : Carcinoma, Hepatocellular, Adult, STAT3 Transcription Factor, Carcinoma, Hepatocellular, MESH : Interleukin-6, MESH : Models, Molecular, MESH : Male, Immunology, Active Transport, Cell Nucleus, Biology, IFN, Adenoma, Liver Cell, gp130, 03 medical and health sciences, MESH : Adenoma, Liver Cell, MESH : Protein Structure, Quaternary, Cell Line, Tumor, medicine, Humans, MESH : Middle Aged, Protein Structure, Quaternary, MESH : Active Transport, Cell Nucleus, Aged, 030304 developmental biology, MESH : Signal Transduction, IL-6, Base Sequence, MESH : Cell Line, Tumor, Interleukin-6, MESH : Humans, Brief Definitive Report, beta-catenin, digestive system diseases, STAT protein, Inflammatory Hepatocellular Adenoma, Cancer research, Tyrosine, MESH : src-Family Kinases, MESH : Base Sequence, Mutant Proteins, Carcinogenesis
Abstract: Somatic STAT3 mutations present in a subset of inflammatory hepatocellular adenomas result in the generation of constitutively active STAT3 proteins that homodimerize independently of IL-6 stimulation., Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.
Published: 2011
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7. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency)

Author: Pierre Bordigoni, Danielle Canioni, Michèle Milili, Nathalie Lambert, Claire Galambrun, Marie Ouachée-Chardin, Filomeen Haerynck, Françoise Le Deist, Despina Moshous, Christelle Lenoir, Stephanie Rigaud, Lionel Galicier, Fabien Touzot, Capucine Picard, Mohamed Hamidou, Hirokazu Kanegane, Ester Mejstrikova, Helen Chapel, Eduardo López-Granados, Stéphane Blanche, Alain Dabadie, Jana Pachlopnik Schmid, Pierre-Simon Rohrlich, Fabian Hauck, Geneviève de Saint Basile, Claudin Schiff, Jean-Louis Stephan, Alain Fischer, Isabelle Pellier, Nizar Mahlaoui, Sylvain Latour, Alain Fourmaintraux, Vincent Barlogis, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Graduate School of Medicine, University of Toyama, Department of pediatrics, University of Oxford [Oxford], Teaching Hospital Motol and 2nd Medical School, Charles University, Department of Pediatric Hematology and Oncology, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'immuno-hématologie pédiatrique [CHU Necker], Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Groupe Hospitalier Sud Réunion (GHSR), Centre Hospitalier Universitaire [Rennes], Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Department of Paediatric Pulmonology, Ghent University Hospital, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de pédiatrie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, CHU Saint-Etienne, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'étude des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Service d'Immunologie et d'Hématologie Pédiatrique, Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), University of Oxford, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Collège de France - Chaire Médecine expérimentale (A. Fischer), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Groupe Hospitalier Sud Réunion ( GHSR ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)
Subjects: Male, MESH : Retrospective Studies, MESH: X-Linked Inhibitor of Apoptosis Protein, MESH : Aged, MESH : Child, Preschool, Biochemistry, Cohort Studies, Immunoenzyme Techniques, Hypogammaglobulinemia, MESH: Lymphoproliferative Disorders, 0302 clinical medicine, MESH : Child, MESH: Child, hemic and lymphatic diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, XIAP Deficiency, Signaling Lymphocytic Activation Molecule Associated Protein, X-Linked Lymphoproliferative Syndrome, Child, MESH: Cohort Studies, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH : Lymphoproliferative Disorders, Intracellular Signaling Peptides and Proteins, MESH : Infant, Hematology, MESH : Adult, Middle Aged, MESH : Survival Rate, MESH: Infant, 3. Good health, Survival Rate, MESH : Phenotype, Phenotype, MESH: Young Adult, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Mutation, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Survival Rate, MESH : Male, Immunology, MESH : Young Adult, MESH : Cohort Studies, X-Linked Inhibitor of Apoptosis Protein, Biology, MESH: Phenotype, Virus, Young Adult, 03 medical and health sciences, MESH : Intracellular Signaling Peptides and Proteins, MESH : Immunoenzyme Techniques, MESH : Adolescent, MESH: Intracellular Signaling Peptides and Proteins, medicine, Humans, MESH : Middle Aged, MESH: Immunoenzyme Techniques, Aged, Retrospective Studies, 030304 developmental biology, MESH: Adolescent, Hemophagocytic lymphohistiocytosis, Cytopenia, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, X-linked lymphoproliferative disease, MESH: Adult, MESH: Retrospective Studies, Cell Biology, medicine.disease, Lymphoproliferative Disorders, MESH: Male, MESH : X-Linked Inhibitor of Apoptosis Protein, Mutation, Histopathology, MESH: Female, 030215 immunology
Abstract: X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.
Published: 2011
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8. A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours

Author: Fabienne Escande, Jean Michel Coindre, Silvana Pilotti, Sébastien Forget, Paolo Dei Tos, Pierre Paul Bringuier, Maria Debiec-Rychter, Elena Tamborini, David Gonzalez, Nicolas Faur, L Morzuch, Isabelle Hostein, Louisa Toffolati, Sylvianne Olschwang, Jean-François Emile, Département de pathologie, Institut Bergonié - CRLCC Bordeaux, university of leuven, Department of Human Genetics, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CA foncello Hospital, Department of pathology, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Laboratoire de Physique des Lasers ( LPL ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut Galilée-Centre National de la Recherche Scientifique ( CNRS ), biology and pathological laboratory, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Service de Pathologie, Institut Bergonié, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, UNICANCER, Radboud University Medical Center [Nijmegen], Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des Lasers (LPL), Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Medical University of Gdańsk, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay
Subjects: Oncology, Receptor, Platelet-Derived Growth Factor alpha, MESH : Polymorphism, Genetic, MESH: Receptor, Platelet-Derived Growth Factor alpha, DNA Mutational Analysis, MESH: Quality Control, MESH : Genotype, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, MESH : Exons, 0302 clinical medicine, Surgical oncology, Genotype, MESH: DNA Mutational Analysis, 0303 health sciences, Mutation, MESH : Gastrointestinal Stromal Tumors, GiST, Gastroenterology, MESH : Quality Control, DNA, Neoplasm, Exons, 3. Good health, MESH: Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-kit, 030220 oncology & carcinogenesis, MESH: Laboratories, MESH : DNA, Neoplasm, MESH : Mutation, MESH: Gastrointestinal Stromal Tumors, Quality Control, medicine.medical_specialty, MESH: Mutation, Gastrointestinal Stromal Tumors, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, PDGFRA, Biology, MESH : Laboratories, MESH : Proto-Oncogene Proteins c-kit, 03 medical and health sciences, Internal medicine, MESH: Polymorphism, Genetic, medicine, Humans, Genotyping, 030304 developmental biology, MESH: Humans, Polymorphism, Genetic, MESH : Humans, Hepatology, digestive system diseases, Immunology, MESH : Receptor, Platelet-Derived Growth Factor alpha, MESH: Exons, Laboratories
Abstract: International audience; BACKGROUND: Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease. METHOD: To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports. RESULTS: In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected. CONCLUSION: This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient.
Published: 2011
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9. Truncation of PITX2 differentially affects its activity on physiological targets

Author: Véronique Vieira, Maurice Menasche, James P. Herman, Thierry Brue, Alain Enjalbert, Marc Abitbol, Marie-Helene Quentien, Jean-Louis Dufier, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche thérapeutique en ophtalmologie, Université Paris Descartes - Paris 5 (UPD5)-EA2502, EA no 2502 du ministère de la Recherche, de l'Enseignement Supérieur et la Technologie, Université Paris Descartes - Paris 5 (UPD5)-CERTO, Service d'ophtalmologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre d'étude et de recherche thérapeutiques en ophtalmologie, Université Paris Descartes - Paris 5 (UPD5), Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - EA2502, Université Paris Descartes - Paris 5 (UPD5) - CERTO, Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: MESH : Cell Line, MESH : Transcription Factors, MESH : Transcription Factor Pit-1, Mutant, Electrophoretic Mobility Shift Assay, MESH : Blotting, Western, MESH : Promoter Regions, Genetic, medicine.disease_cause, MESH : Pituitary Gland, 0302 clinical medicine, Endocrinology, MESH : Prolactin, MESH: Pituitary Gland, MESH: Human Growth Hormone, MESH: Animals, MESH : Transcriptional Activation, MESH : Homeodomain Proteins, Eye Abnormalities, Promoter Regions, Genetic, 0303 health sciences, Mutation, MESH: Anterior Eye Segment, Human Growth Hormone, Eye Diseases, Hereditary, MESH: Transcription Factors, Transfection, MESH: Eye Abnormalities, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Cell biology, MESH : Electrophoretic Mobility Shift Assay, Pituitary Gland, MESH : Mutation, Transcription Factor Pit-1, hormones, hormone substitutes, and hormone antagonists, Transcriptional Activation, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, MESH: Mutation, Blotting, Western, MESH: Prolactin, Biology, MESH : Anterior Eye Segment, Cell Line, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 03 medical and health sciences, stomatognathic system, Anterior Eye Segment, Internal medicine, MESH : Eye Abnormalities, MESH: Promoter Regions, Genetic, MESH: Homeodomain Proteins, medicine, MESH: Blotting, Western, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH : Human Growth Hormone, Molecular Biology, Transcription factor, Gene, 030304 developmental biology, Homeodomain Proteins, Reporter gene, MESH: Humans, POU domain, MESH : Humans, Promoter, MESH: Cell Line, Prolactin, stomatognathic diseases, MESH: Electrophoretic Mobility Shift Assay, 030221 ophthalmology & optometry, MESH: Transcriptional Activation, MESH : Animals, sense organs, MESH: Transcription Factor Pit-1, Transcription Factors
Abstract: International audience; The bicoid-like transcription factor PITX2 has been previously described to interact with the pituitary-specific POU homeodomain factor POU1F1 (human ortholog of PIT-1) to achieve cell-specific expression of prolactin (PRL) and GH in pituitary somatolactotroph cells. In this work, we have investigated the functional properties of three PITX2 mutants reported in Axenfeld-Rieger syndrome patients relative to the regulation of these genes, using reporter genes under the control of human PRL (hPRL), hGH, or POU1F1 promoters transfected in nonpituitary and pituitary cell lines. Among the three mutations studied, Y167X and E101X introduce a premature stop codon, and F104L leads to an amino acid substitution. While PITX2(E101X) is not expressed in the cells following transfection, and PITX2(F104L) is functionally inactive, the PITX2(Y167X) mutant keeps its DNA-binding capacity and displays a markedly enhanced activation of the hPRL and POU1F1 promoters, but not of the hGH promoter. Y167X is the first mutation of PITX2 described to result in a differential effect on the activation of its different physiological targets, hPRL and POU1F1 on one hand and hGH on the other hand. The differential effect of the Y167X mutation might be linked to an interaction of PITX2 with different transcription factors or cofactors when bound to the hPRL and POU1F1 or the hGH promoters. These results might form the basis for the identification of the PITX2 protein complex necessary for the differential GH or PRL expression.
Published: 2010
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10. Trm112p Is a 15-kDa Zinc Finger Protein Essential for the Activity of Two tRNA and One Protein Methyltransferases in Yeast

Author: Léon Dirick, Bruno Lapeyre, Glenn R. Björk, Marie-Hélène Mazauric, Suresh K. Purushothaman, Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Proteomics, MESH : DNA, MESH: tRNA Methyltransferases, MESH : Saccharomyces cerevisiae, MESH : Models, Genetic, Biochemistry, MESH: Recombinant Proteins, MESH : Proteomics, MESH: Saccharomyces cerevisiae Proteins, MESH : Anticodon, RNA, Transfer, MESH : Catalysis, MESH: Models, Genetic, Zinc finger, tRNA Methyltransferases, MESH : Cell Nucleus, 0303 health sciences, MESH : Chromatin, MESH: Proteomics, 030302 biochemistry & molecular biology, MESH: DNA, Zinc Fingers, MESH : Protein Binding, Translation (biology), MESH: Saccharomyces cerevisiae, MESH : Mitosis, Chromatin, Recombinant Proteins, MESH : tRNA Methyltransferases, Transfer RNA, T arm, MESH : Mutation, Protein Binding, MESH: Cell Nucleus, TRNA modification, Saccharomyces cerevisiae Proteins, MESH: Mutation, MESH : Recombinant Proteins, Saccharomyces cerevisiae, Mitosis, MESH : RNA, Transfer, Biology, Catalysis, Chromatin remodeling, MESH: Chromatin, MESH : Saccharomyces cerevisiae Proteins, 03 medical and health sciences, Anticodon, MESH: Anticodon, MESH: Zinc Fingers, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Zinc Fingers, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, Cell Nucleus, Models, Genetic, TRNA Methyltransferase, DNA, Cell Biology, MESH: Mitosis, MESH: Catalysis, MESH: RNA, Transfer, biology.organism_classification, Mutation, RNA
Abstract: International audience; The degenerate base at position 34 of the tRNA anticodon is the target of numerous modification enzymes. In Saccharomyces cerevisiae, five tRNAs exhibit a complex modification of uridine 34 (mcm(5)U(34) and mcm(5)s(2)U(34)), the formation of which requires at least 25 different proteins. The addition of the last methyl group is catalyzed by the methyltransferase Trm9p. Trm9p interacts with Trm112p, a 15-kDa protein with a zinc finger domain. Trm112p is essential for the activity of Trm11p, another tRNA methyltransferase, and for Mtq2p, an enzyme that methylates the translation termination factor eRF1/Sup45. Here, we report that Trm112p is required in vivo for the formation of mcm(5)U(34) and mcm(5)s(2)U(34). When produced in Escherichia coli, Trm112p forms a complex with Trm9p, which renders the latter soluble. This recombinant complex catalyzes the formation of mcm(5)U(34) on tRNA in vitro but not mcm(5)s(2)U(34). An mtq2-0 trm9-0 strain exhibits a synthetic growth defect, thus revealing the existence of an unexpected link between tRNA anticodon modification and termination of translation. Trm112p is associated with other partners involved in ribosome biogenesis and chromatin remodeling, suggesting that it has additional roles in the cell.
Published: 2010
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11. High Prevalence and Fixation of Plasmodium vivax dhfr/dhps Mutations Related to Sulfadoxine/Pyrimethamine Resistance in French Guiana

Author: Stéphane Picot, Thierry Fusai, Magali Tichit, Lise Musset, Eric Legrand, Sébastien Briolant, Christiane Bouchier, Didier Menard, Céline Barnadas, Christophe Rogier, Radicaux Libres, Substrats Énergétiques et Physiopathologie Cérébrale, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon, Laboratoire de parasitologie-mycologie EA 209 - Transports membranaires et chimiorésistances, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire de parasitologie - CNR Paludisme, Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ), Génomique (Plate-Forme), Institut Pasteur [Paris], Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur de Madagascar, Institut Pasteur de Madagascar-Réseau International des Instituts Pasteur ( RIIP ), Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Génomique (Plate-Forme) - Genomics Platform, Institut de Médecine Tropicale du Service de Santé des Armées-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR - laboratoire associé), Laboratoire de Parasitologie [Cayenne, Guyane française], Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), and CNR Paludisme - Laboratoire associé pour la Région Antilles-Guyane
Subjects: medicine.medical_treatment, MESH : Tetrahydrofolate Dehydrogenase, Plasmodium vivax, Drug Resistance, DHPS, MESH: Tetrahydrofolate Dehydrogenase, Drug resistance, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Animals, MESH: Dihydropteroate Synthase, 0303 health sciences, education.field_of_study, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Plasmodium vivax, 3. Good health, Drug Combinations, Pyrimethamine, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH : Drug Combinations, Infectious Diseases, MESH : Plasmodium vivax, MESH: Drug Resistance, MESH : Mutation, MESH : Dihydropteroate Synthase, medicine.drug, MESH: Mutation, MESH: Pyrimethamine, Sulfadoxine, 030231 tropical medicine, Population, Biology, Polymorphism, Single Nucleotide, MESH : Sulfadoxine, Antimalarials, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Virology, parasitic diseases, medicine, Animals, MESH : Pyrimethamine, education, MESH: Drug Combinations, Dihydropteroate Synthase, MESH : Drug Resistance, 030306 microbiology, biology.organism_classification, MESH: Antimalarials, Sulfadoxine/pyrimethamine, Tetrahydrofolate Dehydrogenase, Mutation, MESH : Antimalarials, Parasitology, MESH : Animals, Dihydropteroate synthase, MESH: Sulfadoxine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Plasmodium vivax isolates from French Guiana were studied for the presence of mutations associated with sulfadoxine/pyrimethamine (SP) drug resistance. Ninety-six blood samples were collected from 2000 to 2005 from symptomatic malaria patients. SP drug resistance was predicted by determining point mutations in the dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) genes. All samples showed mutant genotypes in both genes with a prevalence > 90% for the 58R, 117N, 382C, and 383G. A new mutation (116G) in pvdhfr was found at a frequency of 3.3%. Six different pvdhfr/dhps multilocus genotypes were observed with the predominance of the quintuple mutant-type 58R/117N/173L-382C/383G (59.3%). No significant differences were observed between the prevalence of haplotypes and the year of collection. Our results indicate that, in this area, the fixation of SP drug-resistant parasites in the P. vivax population is stable.
Published: 2009
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12. Murine APOBEC1 Is a Powerful Mutator of Retroviral and Cellular RNA In Vitro and In Vivo

Author: Denise Guetard, Marc Sitbon, Jean-Pierre Vartanian, Anne Keriel, Myrtille Renard, Simon Wain-Hobson, Vincent Petit, Rétrovirologie Moléculaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Hypoxanthine Phosphoribosyltransferase, MESH : Molecular Sequence Data, MESH : RNA, Messenger, MESH : DNA, Complementary, MESH : NIH 3T3 Cells, viruses, Muscle Proteins, MESH: Base Sequence, Nucleic Acid Denaturation, MESH : Retroviridae Infections, MESH: Animals, Newborn, Mice, chemistry.chemical_compound, MESH : Hypoxanthine Phosphoribosyltransferase, Structural Biology, Murine leukemia virus, MESH : RNA, MESH: Animals, APOBEC Deaminases, MESH : Cytidine Deaminase, Gammaretrovirus, MESH : Muscle Proteins, 0303 health sciences, biology, Nucleotides, MESH : Animals, Newborn, 030302 biochemistry & molecular biology, MESH: Leukemia Virus, Murine, Cytidine, Cytidine deaminase, MESH: Apolipoproteins B, 3. Good health, Leukemia Virus, Murine, MESH: Retroviridae Infections, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH : Mutation, MESH: Genome, Viral, MESH : Genome, Viral, MESH : Leukemia Virus, Murine, MESH : Nucleic Acid Denaturation, APOBEC, DNA, Complementary, MESH: Mutation, APOBEC-1 Deaminase, Molecular Sequence Data, MESH: Leukemia, Experimental, Genome, Viral, MESH: Nucleic Acid Denaturation, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Muscle Proteins, 03 medical and health sciences, MESH: RNA, Cytidine Deaminase, MESH : Mice, MESH : RNA Editing, Animals, Humans, MESH: RNA Editing, RNA, Messenger, MESH: Mice, Molecular Biology, Apolipoproteins B, MESH: RNA, Messenger, MESH: Cytidine Deaminase, 030304 developmental biology, Messenger RNA, Leukemia, Experimental, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, APOBEC1, MESH : Humans, MESH: Tumor Virus Infections, RNA, MESH : Apolipoproteins B, MESH: DNA, Complementary, biology.organism_classification, MESH: Hypoxanthine Phosphoribosyltransferase, Molecular biology, MESH: Nucleotides, Tumor Virus Infections, Animals, Newborn, chemistry, Mutation, NIH 3T3 Cells, MESH : Nucleotides, MESH : Leukemia, Experimental, MESH : Base Sequence, MESH : Animals, RNA Editing, MESH : Tumor Virus Infections, Retroviridae Infections, MESH: NIH 3T3 Cells
Abstract: International audience; Mammalian APOBEC molecules comprise a large family of cytidine deaminases with specificity for RNA and single-stranded DNA (ssDNA). APOBEC1s are invariably highly specific and edit a single residue in a cellular mRNA, while the cellular targets for APOBEC3s are not clearly established, although they may curtail the transposition of some retrotransposons. Two of the seven member human APOBEC3 enzymes strongly restrict human immunodeficiency virus type 1 in vitro and in vivo. We show here that ssDNA hyperediting of an infectious exogenous gammaretrovirus, the Friend-murine leukemia virus, by murine APOBEC1 and APOBEC3 deaminases occurs in vitro. Murine APOBEC1 was able to hyperdeaminate cytidine residues in murine leukemia virus genomic RNA as well. Analysis of the edited sites shows that the deamination in vivo was due to mouse APOBEC1 rather than APOBEC3. Furthermore, murine APOBEC1 is able to hyperedit its primary substrate in vivo, the apolipoprotein B mRNA, and a variety of heterologous RNAs. In short, murine APOBEC1 is a hypermutator of both RNA and ssDNA in vivo, which could exert occasional side effects upon overexpression.
Published: 2009
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13. Interaction of the coiled‐coil domain with glycosaminoglycans protects angiopoietin‐like 4 from proteolysis and regulates its antiangiogenic activity

Author: Sylvie Ricard-Blum, Clément Faye, Corinne Ardidie-Robouant, Clémence Chomel, Laurent Muller, Stéphane Germain, Aurélie Cazes, A. Barret, Catherine Monnot, Elisa Gomez, Marine Bignon, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Vascular Genomics Network (http://www.evgn.org) (contract LSHMCT-2003-503254), ANR-06-JCJC-0160,ANGPTL4,Role of ANGPTL4 during development and ischemic heart disease(2006), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Experimental Medicine Unit, Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Service d'hématologie A [CHU HEGP], and ANR-06-JCJC-0160,ANGPTL4,Role of ANGPTL4 during development and ischemic heart disease ( 2006 )
Subjects: MESH : Cell Line, MESH : Angiopoietins, Protein Conformation, Angiogenesis, MESH: Cricetinae, Biochemistry, Extracellular matrix, angiogenesis, MESH: Protein Structure, Tertiary, MESH: Protein Conformation, 0302 clinical medicine, MESH : Lipid Metabolism, Cricetinae, MESH: Animals, MESH : Protein Conformation, Glycosaminoglycans, MESH: Lipid Metabolism, 0303 health sciences, MESH : Neovascularization, Physiologic, medicine.diagnostic_test, Chemistry, MESH : Cricetinae, MESH : Extracellular Matrix, MESH : Protein Binding, MESH: Glycosaminoglycans, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Cell biology, Endothelial stem cell, 030220 oncology & carcinogenesis, endothelial cell, MESH : Mutation, MESH : Protein Structure, Tertiary, MESH: Neovascularization, Physiologic, Protein Binding, Biotechnology, MESH: Mutation, extracellular matrix, Proteolysis, Neovascularization, Physiologic, Angiopoietin-like 4 Protein, MESH: Extracellular Matrix, Cell Line, Angiopoietin, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Glycosaminoglycans, Genetics, medicine, Animals, Humans, MESH: Protein Binding, Molecular Biology, 030304 developmental biology, MESH: Humans, hypoxia, MESH : Humans, Lipid Metabolism, Protein Structure, Tertiary, MESH: Cell Line, Cell culture, MESH: Angiopoietins, Mutation, MESH : Animals, Proprotein Convertases, Angiopoietins
Abstract: International audience; Angiopoietin-like 4 (ANGPTL4) is involved in angiogenesis and lipid metabolism. It is secreted by liver and adipose tissues and cleaved to generate circulating coiled-coil domain (CCD) and fibrinogen-like domain (FLD) fragments. The full-length ANGPTL4 produced by hypoxic endothelial cells interacts with the extracellular matrix (ECM). The ECM-bound and soluble forms of ANGPTL4 have antiangiogenic properties. We carried out a structure-function analysis to investigate the regulation of ANGPTL4 bioactivity in endothelial cells. We found that the recombinant CCD binds to the ECM, whereas the FLD is released into the medium. The CCD, like the full-length ANGPTL4, binds to heparan and dermatan sulfates in surface plasmon resonance assays and inhibits endothelial cell adhesion, motility, and tubule-like formation. In endothelial cells, ANGPTL4 is processed in the secretion medium after release from the ECM. This processing is altered by the proprotein convertases inhibitor alpha1-PDX and abolished by the mutation of the (161)RRKR(164) cleavage site without modification of the ECM binding and release. These data suggest that the full-length form, which interacts with heparan sulfate proteoglycans via its CCD, is protected from proteolysis by proprotein convertases and constitutes the major active pool of ANGPTL4 in hypoxic endothelial cells.
Published: 2008
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14. Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity

Author: Sami Al-Hajjar, Carlos Rodríguez-Gallego, John I. Gallin, Toshiro Hara, Maya Chrabieh, Andrew C. Issekutz, Huey Hsuan Chang, Horst von Bernuth, Joanne Smart, Helen Chapel, Eric Vivier, László Maródi, David P. Speert, Mimi L.K. Tang, Jean-Laurent Casanova, Capucine Picard, Xiaoxia Li, Steven M. Holland, Shen-Ying Zhang, Franck J. Barrat, Stephan Ehl, Abdulaziz Al-Ghonaium, Ben Zion Garty, Chaim M. Roifman, Xavier Bossuyt, Douglas R. McDonald, Anne Puel, Hidetoshi Takada, Ofer Levy, Damien Sanlaville, Laurent Abel, Frederic Geissmann, Richard L. Miller, Cheng-Lung Ku, Kun Yang, Noorbibi K. Day-Good, Coleen K. Cunningham, Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Interactions cellulaires neuroendocriniennes ( ICN ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and University of Groningen
Subjects: Male, Myeloid, Lipopolysaccharide, MESH : Cytokines, medicine.medical_treatment, MESH : Leukocytes, MESH : Child, Preschool, chemistry.chemical_compound, 0302 clinical medicine, MESH : Child, MESH: Child, Leukocytes, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Myeloid Cells, MESH : Female, Child, Cells, Cultured, MESH: Cytokines, 0303 health sciences, Toll-like receptor, MESH : Gene Expression Regulation, Interleukin, Cell Differentiation, PNEUMOCOCCAL MENINGITIS, MESH : Infant, Bacterial Infections, Articles, MYELOID DIFFERENTIATION FACTOR-88, MESH : Adult, MESH: Infant, MESH: Gene Expression Regulation, C-REACTIVE PROTEIN, Pedigree, 3. Good health, MESH : Bacterial Infections, Interleukin-1 Receptor-Associated Kinases, medicine.anatomical_structure, Cytokine, Child, Preschool, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Mutation, MESH : Cell Differentiation, IRAK4 KINASE-ACTIVITY, MESH: Toll-Like Receptors, MESH: Cells, Cultured, Adult, MESH: Cell Differentiation, MESH: Mutation, Adolescent, MESH : Myeloid Cells, MESH: Pedigree, MESH: Bacterial Infections, MESH : Male, Immunology, Biology, Article, MESH: Interleukin-1 Receptor-Associated Kinases, MESH: Leukocytes, IL-1 RECEPTOR, 03 medical and health sciences, Immunity, MESH : Adolescent, MESH : Cells, Cultured, medicine, Humans, 030304 developmental biology, TOLL-LIKE RECEPTORS, MESH: Adolescent, CUTTING EDGE, MESH: Humans, Innate immune system, MESH : Humans, MESH: Child, Preschool, HERPES-SIMPLEX-VIRUS, Infant, MESH: Adult, medicine.disease, MESH: Myeloid Cells, MESH: Male, Gene Expression Regulation, chemistry, MESH : Pedigree, MESH : Toll-Like Receptors, Mutation, PLASMACYTOID DENDRITIC CELLS, INNATE IMMUNITY, Primary immunodeficiency, MESH : Interleukin-1 Receptor-Associated Kinases, MESH: Female, 030215 immunology
Abstract: Human interleukin ( IL) 1 receptor - associated kinase 4 ( IRAK- 4) deficiency is a recently discovered primary immunodefi ciency that impairs Toll/ IL- 1R immunity, except for the Toll- like receptor ( TLR) 3 - and TLR4 - interferon ( IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK- 4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells ( PBMCs) did not induce the 11 non- IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly( I: C). The patients' individual cell subsets from both myeloid ( granulocytes, monocytes, monocyte- derived dendritic cells [ MDDCs], myeloid DCs [ MDCs], and plasmacytoid DCs) and lymphoid ( B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly( I: C) and lipopolysaccharide in MDCs and MDDCs. Most patients ( 22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent ( 13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease ( 9 out of 28; 32%). Almost half of the patients died ( 12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK- 4 - dependent TLRs and IL- 1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK- 4 - dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
Published: 2007
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15. Matthew-Wood Syndrome Is Caused by Truncating Mutations in the Retinol-Binding Protein Receptor Gene STRA6

Author: Michel Vekemans, Christelle Golzio, Bettina Grattagliano-Bessières, Jelena Martinovic-Bouriel, Arnold Munnich, Sophie Delahaye, Tania Attié-Bitach, Stanislas Lyonnet, Heather C. Etchevers, Soumaya Mougou-Zrelli, Maryse Bonnière, Férechté Encha-Razavi, Sophie Thomas, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Institut de Puériculture de Paris (IPP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Puériculture de Paris ( IPP ), and Assistance publique - Hôpitaux de Paris (AP-HP)
Subjects: Lung Diseases, MESH: Sequence Analysis, DNA, Vitamin A transport, MESH : Polymorphism, Genetic, MESH : Receptors, Cell Surface, MESH : Gene Deletion, MESH: Genetic Markers, MESH : Syndrome, MESH : Frameshift Mutation, MESH : Microphthalmos, Consanguinity, MESH: Lung Diseases, Exon, MESH : Exons, 0302 clinical medicine, Microphthalmos, MESH : Genetic Markers, MESH: Syndrome, Genetics(clinical), Frameshift Mutation, Genetics (clinical), MESH: Receptors, Cell Surface, 0303 health sciences, Fetal Growth Retardation, MESH : Lung Diseases, Homozygote, MESH: Frameshift Mutation, Exons, Syndrome, Pedigree, MESH: Membrane Proteins, MESH : Mutation, MESH: Homozygote, Genetic Markers, MESH: Abnormalities, Multiple, MESH: Mutation, MESH: Pedigree, MESH: Microphthalmos, MESH: Fetal Growth Retardation, Receptors, Cell Surface, Biology, Frameshift mutation, 03 medical and health sciences, Pulmonary hypoplasia, MESH : Homozygote, Report, MESH : Consanguinity, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, Abnormalities, Multiple, MESH : Fetal Growth Retardation, MESH : Haplotypes, 030304 developmental biology, MESH: Consanguinity, MESH : Mutagenesis, Insertional, Polymorphism, Genetic, MESH: Humans, Anophthalmia, MESH : Abnormalities, Multiple, Genetic heterogeneity, MESH : Humans, Pulmonary Agenesis, Membrane Proteins, Sequence Analysis, DNA, MESH: Haplotypes, medicine.disease, Molecular biology, Mutagenesis, Insertional, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Haplotypes, MESH: Mutagenesis, Insertional, MESH : Membrane Proteins, MESH: Gene Deletion, MESH : Pedigree, [ SDV.BDD.EO ] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Mutation, MESH: Exons, Matthew Wood syndrome, Gene Deletion, 030217 neurology & neurosurgery, MESH : Sequence Analysis, DNA
Abstract: International audience; Retinoic acid (RA) is a potent teratogen in all vertebrates when tight homeostatic controls on its endogenous dose, location, or timing are perturbed during early embryogenesis. STRA6 encodes an integral cell-membrane protein that favors RA uptake from soluble retinol-binding protein; its transcription is directly regulated by RA levels. Molecular analysis of STRA6 was undertaken in two human fetuses from consanguineous families we previously described with Matthew-Wood syndrome in a context of severe microphthalmia, pulmonary agenesis, bilateral diaphragmatic eventration, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation. The fetuses had either a homozygous insertion/deletion in exon 2 or a homozygous insertion in exon 7 predicting a premature stop codon in STRA6 transcripts. Five other fetuses presenting at least one of the two major signs of clinical anophthalmia or pulmonary hypoplasia with at least one of the two associated signs of diaphragmatic closure defect or cardiopathy had no STRA6 mutations. These findings suggest a molecular basis for the prenatal manifestations of Matthew-Wood syndrome and suggest that phenotypic overlap with other associations may be due to genetic heterogeneity of elements common to the RA- and fibroblast growth factor-signaling cascades.
Published: 2007
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16. Next-generation sequencing offers new insights into the resistance of Candida spp. to echinocandins and azoles

Author: Danièle Maubon, Christophe Hennequin, Cécile Garnaud, Marie-Elisabeth Bougnoux, Natacha Sertour, Françoise Botterel, Sylvie Larrat, Muriel Cornet, Jesús Guinea, Eric Dannaoui, Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de Parasitologie-Mycologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Parasitologie - Mycologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Clinical Microbiology and Infectious Diseases Department, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), This work was supported by a grant from Pfizer (Prix de recherche Société Française de Mycologie Médicale—Pfizer 2012). The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript., Thérapeutique Recombinante Expérimentale ( TIMC-IMAG-THEREX ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut National de la Recherche Agronomique ( INRA ) -Institut Pasteur [Paris], Dynamyc Mycology - EA 7380, Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Laboratoire de biologie structurale des interactions entre virus et cellule hôte, Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie et Pathologie [CHU Grenoble] ( IBP ), CHU Grenoble-Université Grenoble Alpes ( UGA ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Universidad Complutense de Madrid [Madrid] ( UCM ), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Dynamyc- Dynamyc Mycology - EA 7380, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Universidad Complutense de Madrid [Madrid] (UCM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Azoles, Antifungal Agents, MESH : Genotype, Candida parapsilosis, MESH: Genotype, chemistry.chemical_compound, MESH : Candidiasis, Echinocandins, MESH: Azoles, Pharmacology (medical), Candida albicans, MESH: High-Throughput Nucleotide Sequencing, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Candida, Genetics, chemistry.chemical_classification, 0303 health sciences, biology, Candidiasis, High-Throughput Nucleotide Sequencing, Caspofungin Acetate, MESH: Candidiasis, Infectious Diseases, NGS, MESH : Mutation, antifungals, medicine.drug, Microbiology (medical), MESH: Mutation, Echinocandin, Genotype, MESH : Antifungal Agents, Microbiology, MESH: Drug Resistance, Fungal, 03 medical and health sciences, Drug Resistance, Fungal, MESH: Candida, medicine, Humans, 030304 developmental biology, MESH : Echinocandins, Pharmacology, MESH: Humans, Candida glabrata, 030306 microbiology, MESH: Echinocandins, MESH : Humans, MESH : Drug Resistance, Fungal, biology.organism_classification, mutations, MESH: Antifungal Agents, MESH : Azoles, chemistry, Mutation, Azole, Caspofungin, MESH : Candida, MESH : High-Throughput Nucleotide Sequencing
Abstract: International audience; ObjectivesMDR Candida strains are emerging. Next-generation sequencing (NGS), which enables extensive and deep genome analysis, was used to investigate echinocandin and azole resistance in clinical Candida isolates.; MethodsSix genes commonly involved in antifungal resistance (ERG11, ERG3, TAC1, CgPDR1, FKS1 and FKS2) were analysed using NGS in 40 Candida isolates (18 Candida albicans, 15 Candida glabrata and 7 Candida parapsilosis). The strategy was validated using strains with known sequences. Then, 8 clinical strains displaying antifungal resistance and 23 sequential isolates collected from 10 patients receiving antifungal therapy were analysed.; ResultsA total of 391 SNPs were detected, among which 6 coding SNPs were reported for the first time. Novel genetic alterations were detected in both azole and echinocandin resistance genes. A C. glabrata strain, which was resistant to echinocandins but highly susceptible to azoles, harboured an FKS2 S663P mutation plus a novel presumed loss-of-function CgPDR1 mutation. This isolate was from a patient with deep-seated and urinary candidiasis. Another C. glabrata isolate, with an MDR phenotype, carried a new FKS2 S663A mutation and a new putative gain-of-function CgPDR1 mutation (T370I); this isolate showed mutated (80%) and WT (20%) populations and was collected after 75 days of exposure to caspofungin from a patient who underwent complicated abdominal surgery.; ConclusionsThis study shows that NGS can be used for extensive assessment of genetic mutations involved in antifungal resistance. This type of wide genome approach will become very valuable for detecting mechanisms of resistance in clinical strains subjected to multidrug pressure.
Published: 2015
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17. MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance

Author: Julien Messéant, Marin Manuel, Daniel Zytnicki, Alexandre Dobbertin, Laurent Schaeffer, Claire Legay, Alain Schmitt, Perrine Delers, Emmanuelle Girard, Francesca Mangione, Laure Strochlic, Dominique Le Denmat, Jordi Molgó, Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Neurophysique et physiologie du système moteur (NPSM), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut des Neurosciences Paris-Saclay (NeuroPSI), Association Francaise contre les Myopathies (14960, 18046), Centre National de la Recherche Scientifique, Paris Descartes University, Institut National de la Sante et de la Recherche Medicale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de neurophysique, physiologie, pathologie ( UMR 8119 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pathologies, Imagerie et Biothérapies oro-faciales ( EA 2496 ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Neurosciences de Paris-Saclay ( Neuro-PSI ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Neurophysique et physiologie du système moteur ( NPSM ), and Biologie des Jonctions Neuromusculaires Normales et Pathologiques ( U686 )
Subjects: Male, MESH: Fatigue, Frizzled, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH : Muscle Weakness, Synaptogenesis, MESH: Animals, Newborn, Synapse, Mice, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, Receptors, Cholinergic, MESH : Female, MESH: Animals, Fatigue, MuSK, Motor Neurons, 0303 health sciences, Muscle Weakness, synaptogenesis, Hand Strength, neuromuscular junction, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH : Animals, Newborn, General Neuroscience, Intracellular Signaling Peptides and Proteins, Wnt signaling pathway, MESH: Muscle Weakness, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Lithium Chloride, Articles, Congenital myasthenic syndrome, MESH : Mice, Transgenic, MESH : Fatigue, medicine.anatomical_structure, MESH: Hand Strength, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Acetylcholinesterase, Female, MESH: Receptor Protein-Tyrosine Kinases, MESH : Mutation, medicine.symptom, MESH : Lithium Chloride, MESH : Hand Strength, MESH: Motor Neurons, MESH: Myasthenic Syndromes, Congenital, animal structures, MESH: Mutation, MESH : Motor Neurons, MESH: Mice, Transgenic, MESH : Male, Primary Cell Culture, MESH: Glycoproteins, Mice, Transgenic, Biology, MESH : Myasthenic Syndromes, Congenital, Neuromuscular junction, MESH : Acetylcholinesterase, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Primary Cell Culture, 03 medical and health sciences, Wnt, MESH : Mice, medicine, Animals, MESH : Primary Cell Culture, MESH: Mice, lithium chloride, Glycoproteins, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, MESH: Receptors, Cholinergic, Receptor Protein-Tyrosine Kinases, Muscle weakness, MESH : Receptor Protein-Tyrosine Kinases, MESH: Acetylcholinesterase, MESH : Receptors, Cholinergic, medicine.disease, MESH : Glycoproteins, MESH: Male, MESH : Pregnancy, Animals, Newborn, nervous system, congenital myasthenic syndrome, Mutation, MESH : Neuromuscular Junction, MESH : Animals, MESH: Neuromuscular Junction, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract: The muscle-specific kinase MuSK is one of the key molecules orchestrating neuromuscular junction (NMJ) formation. MuSK interacts with the Wnt morphogens, through its Frizzled-like domain (cysteine-rich domain [CRD]). Dysfunction of MuSK CRD in patients has been recently associated with the onset of myasthenia, common neuromuscular disorders mainly characterized by fatigable muscle weakness. However, the physiological role of Wnt-MuSK interaction in NMJ formation and function remains to be elucidated. Here, we demonstrate that the CRD deletion of MuSK in mice caused profound defects of both muscle prepatterning, the first step of NMJ formation, and synapse differentiation associated with a drastic deficit in AChR clusters and excessive growth of motor axons that bypass AChR clusters. Moreover, adultMuSKΔCRDmice developed signs of congenital myasthenia, including severe NMJs dismantlement, muscle weakness, and fatigability. We also report, for the first time, the beneficial effects of lithium chloride, a reversible inhibitor of the glycogen synthase kinase-3, that rescued NMJ defects inMuSKΔCRDmice and therefore constitutes a novel therapeutic reagent for the treatment of neuromuscular disorders linked to Wnt-MuSK signaling pathway deficiency. Together, our data reveal that MuSK CRD is critical for NMJ formation and plays an unsuspected role in NMJ maintenance in adulthood.
Published: 2015
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18. Shifted, the Drosophila Ortholog of Wnt Inhibitory Factor-1, Controls the Distribution and Movement of Hedgehog

Author: Michael A. Halbisen, Bruno Glise, Alain Vincent, Michèle Crozatier, Steve Wise, Catherine A. Miller, David J. Olson, Seth S. Blair, Institut de Recherches et d'Etudes sur le Monde Arabe et Musulman (IREMAM), Sciences Po Aix - Institut d'études politiques d'Aix-en-Provence (IEP Aix-en-Provence)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Anatomopathologie Haut-Lévêque (ANATOMOPATHOLOGIE), CHU, Clinical Neurology Oxford (CLINICAL NEUROLOGY), Hospital, Departement /u661 : Endocrinologie, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de synthèse organique (DCSO), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), FLAveur, VIsion et Comportement du consommateur (FLAVIC), Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Institut de Recherches et d'Etudes sur les Mondes Arabes et Musulmans (IREMAM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches et d'Etudes sur le Monde Arabe et Musulman ( IREMAM ), Sciences Po Aix - Institut d'études politiques d'Aix-en-Provence ( IEP Aix-en-Provence ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de biologie du développement ( CBD ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Bordelais de Recherche en Informatique ( LaBRI ), Centre National de la Recherche Scientifique ( CNRS ) -École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Anatomopathologie Haut-Lévêque ( ANATOMOPATHOLOGIE ), Clinical Neurology Oxford ( CLINICAL NEUROLOGY ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de synthèse organique ( DCSO ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), FLAveur, VIsion et Comportement du consommateur ( FLAVIC ), Etablissement National d'Enseignement Supérieur Agronomique de Dijon ( ENESAD ) -Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Université de Bourgogne (UB)
Subjects: Male, MESH: Signal Transduction, MESH : Molecular Sequence Data, MESH: Sequence Homology, Amino Acid, MESH: Drosophila, MESH : Animals, Genetically Modified, Sequence Homology, MESH : Models, Biological, MESH: Amino Acid Sequence, Wing, MESH: Cholesterol, 0302 clinical medicine, Models, Drosophila Proteins, MESH : Female, MESH: Animals, MESH : Cholesterol, Genetics, 0303 health sciences, biology, MESH : Amino Acid Sequence, Wnt signaling pathway, Signal transducing adaptor protein, MESH : Sequence Homology, Amino Acid, Hedgehog signaling pathway, Cell biology, MESH : Phenotype, Amino Acid, Imaginal disc, Cholesterol, Phenotype, MESH: Repressor Proteins, Drosophila, Female, MESH : Mutation, MESH : Repressor Proteins, MESH : Carrier Proteins, Drosophila melanogaster, Signal transduction, MESH : Heparan Sulfate Proteoglycans, Drosophila Protein, Signal Transduction, MESH: Mutation, animal structures, MESH: Drosophila Proteins, MESH : Male, Molecular Sequence Data, MESH : Wing, Genetically Modified, MESH: Carrier Proteins, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, MESH: Animals, Genetically Modified, 03 medical and health sciences, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, MESH : Drosophila, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Hedgehog, Alleles, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, MESH: Molecular Sequence Data, MESH: Alleles, MESH : Humans, MESH: Models, Biological, Cell Biology, MESH : Drosophila Proteins, Biological, MESH: Wing, biology.organism_classification, MESH: Male, Repressor Proteins, Mutation, MESH: Heparan Sulfate Proteoglycans, MESH : Animals, MESH : Alleles, Carrier Proteins, MESH: Female, Heparan Sulfate Proteoglycans, 030217 neurology & neurosurgery, Developmental Biology
Abstract: SummaryWe here identify and characterize an extracellular modulator of Hedgehog signaling in Drosophila, Shifted. Shifted is required for high levels of long-range signaling in the developing wing imaginal disc. Surprisingly, shifted encodes the only Drosophila ortholog of the secreted vertebrate protein Wnt Inhibitory Factor-1 (WIF-1), whose known role is to bind to extracellular Wnts and inhibit their activity. However, Shifted does not regulate Hedgehog signaling by affecting Wingless or Wnt signaling. We show instead that Shifted is a secreted protein that acts over a long distance and is required for the normal accumulation of Hh protein and its movement in the wing. Our data further indicate that Shf interacts with Hh and the heparan sulfate proteoglycans. Therefore, we propose that Shf stabilizes the interaction between Hh and the proteoglycans, an unexpected role for a member of the WIF-1 family.
Published: 2005
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19. Vein-positioning in the Drosophila wing in response to Hh; new roles of Notch signaling

Author: Michèle Crozatier, Alain Vincent, Bruno Glise, Vanessa Khemici, Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Anatomopathologie Haut-Lévêque (ANATOMOPATHOLOGIE), CHU, Clinical Neurology Oxford (CLINICAL NEUROLOGY), Hospital, Laboratoire de synthèse organique (DCSO), École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), FLAveur, VIsion et Comportement du consommateur (FLAVIC), Institut National de la Recherche Agronomique (INRA)-Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Université de Bourgogne (UB), Centre de biologie du développement ( CBD ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Bordelais de Recherche en Informatique ( LaBRI ), Centre National de la Recherche Scientifique ( CNRS ) -École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Anatomopathologie Haut-Lévêque ( ANATOMOPATHOLOGIE ), Clinical Neurology Oxford ( CLINICAL NEUROLOGY ), Departement /u661 : Endocrinologie, Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de synthèse organique ( DCSO ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), FLAveur, VIsion et Comportement du consommateur ( FLAVIC ), Etablissement National d'Enseignement Supérieur Agronomique de Dijon ( ENESAD ) -Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)
Subjects: MESH: Signal Transduction, Embryology, MESH: Drosophila, MESH : Genotype, MESH : Models, Biological, Wing, MESH: Genotype, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Models, Receptors, MESH: Gene Expression Regulation, Developmental, Wings, Animal, Drosophila Proteins, Developmental, MESH: Animals, In Situ Hybridization, Regulation of gene expression, 0303 health sciences, Receptors, Notch, Rhomboid, Gene Expression Regulation, Developmental, MESH : In Situ Hybridization, Anatomy, Cell biology, Imaginal disc, Drosophila, MESH: Membrane Proteins, MESH : Mutation, MESH : Protein Structure, Tertiary, Drosophila Protein, Signal Transduction, MESH: Body Patterning, Protein Structure, Notch, MESH: Mutation, Genotype, MESH: Drosophila Proteins, Notch signaling pathway, MESH : Wing, Biology, Models, Biological, Veins, 03 medical and health sciences, MESH: In Situ Hybridization, Compartment (development), Animals, Primordium, Hedgehog Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Drosophila, Hedgehog, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Body Patterning, MESH : Signal Transduction, MESH: Veins, MESH : Veins, MESH: Models, Biological, Membrane Proteins, MESH : Body Patterning, MESH : Drosophila Proteins, Biological, MESH: Wing, Protein Structure, Tertiary, Gene Expression Regulation, MESH : Membrane Proteins, MESH : Receptors, Notch, Mutation, MESH : Animals, MESH : Gene Expression Regulation, Developmental, MESH: Receptors, Notch, 030217 neurology & neurosurgery, Tertiary, Developmental Biology
Abstract: The Drosophila wing is a classical model for studying the generation of developmental patterns. Previous studies have suggested that vein primordia form at boundaries between discrete sectors of gene expression along the antero-posterior (A/P) axis in the larval wing imaginal disc. Observation that the vein marker rhomboid (rho) is expressed at the centre of wider vein-competent domains led to propose that narrow vein primordia form first, and produce secondary short-range signals activating provein genes in neighbouring cells (see Curr. Opin. Genet. Dev. 10 (2000) 393). Here, we examined how the central L3 and L4 veins are positioned relative to the limits of expression of Collier (Col), a dose-dependent Hedgehog (Hh) target activated in the wing A/P organiser. We found that rho expression is first activated in broad domains adjacent to Col-expressing cells and secondarily restricted to the centre of these domains. This restriction which depends upon Notch (N) signaling sets the L3 and L4 vein primordia off the boundaries of Col expression. N activity is also required to fix the anterior limit of Col expression by locally antagonising Hh activation, thus precisely positioning the L3 vein primordium relative to the A/P compartment boundary. Experiments using Nts mutants further indicated that these two activities of N could be temporally uncoupled. Together, these observations highlight new roles of N in topologically linking the position of veins to prepattern gene expression.
Published: 2003
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20. Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia

Author: Nizar Ben Halim, Mbarka Bchetnia, Khaled Lasram, Daniele Castiglia, Nadia Laroussi, Sonia Abdelhak, Lilia Romdhane, Rym Kefi, Mounira Meddeb Cherif, Houyem Ouragini, Mohamed Samir Boubaker, Hamida Turki, Ahlem Sabrine Ben Brick, Alain Hovnanian, Salaheddine Marrakchi, Hela Mesrati, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Department of Dermatology, Hedi Chaker Hospital [Sfax], Laboratory of Medical Genetics, Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IRCCS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (Laboratory on ‘‘Biomedical Genomics and Oncogenetics’’ LR11IPT05) and the Tunisian Ministry of Public Health, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory ( LR11IPT05 ), Université Tunis El Manar ( UTM ) -Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), Hedi Chaker Hospital, Istituto Dermopatico dell'Immacolata ( IRCCS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université Tunis El Manar (UTM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Founder Effect, 030207 dermatology & venereal diseases, Consanguinity, 0302 clinical medicine, Recessive dystrophic epidermolysis bullosa, COL7A1, MESH : Epidermolysis Bullosa Dystrophica/genetics, MESH : Female, MESH : Skin/pathology, MESH: DNA Mutational Analysis, MESH : Collagen Type VII/genetics, Skin, Genetics, 0303 health sciences, MESH: Epidermolysis Bullosa Dystrophica/genetics, MESH: Collagen Type VII/genetics, General Medicine, Founder effect, Novel mutations, MESH: Epidermolysis Bullosa Dystrophica/pathology, 3. Good health, Epidermolysis Bullosa Dystrophica, Pedigree, [ SDV.GEN.GPO ] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Codon, Nonsense, Mutation (genetic algorithm), Carcinoma, Squamous Cell, Female, MESH : Mutation, MESH: Tunisia, Collagen Type VII, Tunisia, MESH: Mutation, MESH: Pedigree, MESH : Male, MESH : Founder Effect, Genes, Recessive, Dermatology, MESH : DNA Mutational Analysis, Biology, MESH : Epidermolysis Bullosa Dystrophica/pathology, MESH : Carcinoma, Squamous Cell/complications, 03 medical and health sciences, MESH : Tunisia, MESH : Consanguinity, Humans, Allele, Gene, MESH : Haplotypes, Alleles, MESH: Genes, Recessive, 030304 developmental biology, MESH: Consanguinity, MESH: Skin/pathology, MESH: Codon, Nonsense/genetics, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [ SDV ] Life Sciences [q-bio], MESH: Alleles, Haplotype, MESH : Humans, MESH : Genes, Recessive, MESH: Haplotypes, MESH: Male, MESH : Codon, Nonsense/genetics, MESH: Carcinoma, Squamous Cell/complications, Haplotypes, MESH : Pedigree, Mutation, MESH : Alleles, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, Recessive dystrophic epidermolysis bullosa severe generalized, MESH: Female, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Dystrophic epidermolysis bullosa (DEB) is a group of heritable bullous skin disorders caused by mutations in the COL7A1 gene. One of the most severe forms of DEB is the severe generalized [recessive dystrophic epidermolysis bullosa (RDEB-SG)] subtype, which is inherited in an autosomal recessive manner. This subtype is most often due to COL7A1 mutations resulting in a premature termination codon on both alleles. We report here, the molecular investigation of 15 patients belonging to 14 nuclear families from the city of Sfax in Southern Tunisia, with clinical features of RDEB-SG complicated by squamous cell carcinoma in 3 patients. We identified two novel mutations, p.Val769LeufsX1 and p.Ala2297SerfsX91, in addition to one previously reported mutation (p.Arg2063Trp). The p.Val769LeufsX1 mutation was shared by 11 families and haplotype analysis indicated that it is a founder mutation. The p.Ala2297SerfsX91 mutation was a private mutation found in only one family. Together with the previously described recurrent mutations in Tunisia, screening for the founder p.Val769LeufsX1 mutation should provide a rapid molecular diagnosis tool for mutation screening in RDEB patients from Southern Tunisia and possibly from other Mediterranean populations sharing the same genetic background.
Published: 2014
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21. Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome

Author: Ulrike Zabel, Thomas Wieland, Martin J. Lohse, Fabio R. Faucz, Annalisa Vetro, Andrea Osswald, Guillaume Assié, Cristina L. Ronchi, Thomas Schwarzmayr, Susanne Diener, Caroline Kisker, Bruno Allolio, Tim M. Strom, Silviu Sbiera, Olivia Barreau, Martin Reincke, Delphine Vezzosi, Felix Beuschlein, Jérôme Bertherat, Orsetta Zuffardi, Antonella Forlino, Thomas Meitinger, Martin Fassnacht, Katrin Schaak, Eva Szarek, Constantine A. Stratakis, Anett Schmittfull, Paraskevi Salpea, Davide Calebiro, Marthe Rizk-Rabin, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (LMU), Department of Medicine I, University Hospital, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institute of Pharmacology and Toxicology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Comprehensive Cancer Center Mainfranken, Institute of Human Genetics, Helmholtz-Zentrum München (HZM)-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), University Hospital of Würzburg, Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Medicine [Pavia, Italy] (Unit of Biochemistry), University of Pavia, Human Genetics, Biologia Generale e Genetica Medica, Università degli Studi di Pavia, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, Internal Medicine III, Universität Ulm - Ulm University [Ulm, Allemagne], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Medizinische Klinik - Innenstadt, Department of Psychiatry, Ludwig-Maximilians-Universität München, Comprehensive Heart Failure Center, University of Würzburg-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Endocrine and Diabetes Unit, Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Centre de Référence pour les Maladies Rares, University of Würzburg, Helmholtz-Zentrum München ( HZM ) -Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Dipartimento di Medicina Molecolare, Biotechnology Research Laboratory, Istituti di Ricovero e Cura a Carattere Scientifico ( IRCCS ) -Fondazione I.R.C.C.S. - Policlinico San Matteo, Deutsches Zentrum für Herz-Kreislauf-Forschung partner site, Munich Heart Alliance, Supported by a grant (FP7/2007-2013) from the European Com - mission Seventh Framework Program under grant agreement 259735 (to Drs. Beuschlein, Fassnacht, Bertherat, and Allolio) and, in part, by grants from the Wilhelm Sander-Stiftung (2012.095.1, to Dr. Allolio), the Else Kröner-Fresenius-Stiftung (2012_A103, to Dr. Reincke), Bundesministerium für Bildung und Forschung (BMBF 01EO1004-D2, to Drs. Fassnacht and Allolio), the COMETE Network (Programme Hospitalier de Recherche Clinique grant AOM95201), the Institut National du Cancer Recherche Transla - tionelle 2009-RT-02, INSERM (with Dr. Assié a recipient of a Contrat d'Interface), the Conny-Maeva Charitable Foundation, the European Research Council (Advanced Grant TOPAS, to Dr. Lohse), the Deutsche Forschungsgemeinschaft (DFG) (Ru - dolf Virchow Center and DFG Research Center for Experimen - tal Biomedicine FZT82, to Drs. Kisker and Lohse, and DFG grant CA1014/1-1, to Dr. Calebiro), the Fondazione Telethon 2010 (GGP10121, to Dr. Zuffardi), and the Intramural Research Pro - gram of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence pour les Maladies Rares, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)-Fondazione I.R.C.C.S. - Policlinico San Matteo, Julius-Maximilians-Universität Würzburg (JMU)-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Julius-Maximilians-Universität Würzburg (JMU), Helmholtz Zentrum München = German Research Center for Environmental Health-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Università degli Studi di Pavia = University of Pavia (UNIPV), Bos, Mireille, Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, and Università di Pavia
Subjects: MESH: Adrenal Hyperplasia, Congenital, MESH: Sequence Analysis, DNA, Hydrocortisone, Protein Conformation, MESH : Adrenal Hyperplasia, Congenital, MESH : Germ-Line Mutation, [SDV]Life Sciences [q-bio], Adrenal Gland Neoplasms, MESH: Catalytic Domain, MESH: Cushing Syndrome, Cushing syndrome, 0302 clinical medicine, MESH: Protein Conformation, Catalytic Domain, MESH: Germ-Line Mutation, Exome, Cushing Syndrome, Exome sequencing, MESH : Protein Conformation, MESH : Cushing Syndrome, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Exome, MESH: Middle Aged, Adrenal cortex, MESH : Catalytic Domain, General Medicine, Middle Aged, MESH : Adult, MESH: Hydrocortisone, 3. Good health, MESH : Cyclic AMP-Dependent Protein Kinases, medicine.anatomical_structure, MESH : Mutation, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Adenoma, Adult, endocrine system, MESH: Mutation, MESH : Adrenal Gland Neoplasms, Adrenal Gland Neoplasm, 030209 endocrinology & metabolism, MESH: Cyclic AMP-Dependent Protein Kinases, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Middle Aged, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Germ-Line Mutation, 030304 developmental biology, MESH: Adenoma, MESH: Humans, Adrenal Hyperplasia, Congenital, business.industry, MESH : Humans, MESH : Exome, MESH: Adult, Sequence Analysis, DNA, medicine.disease, Cyclic AMP-Dependent Protein Kinases, MESH: Adrenal Gland Neoplasms, PRKACA, MESH : Adenoma, Mutation, Cancer research, business, MESH : Hydrocortisone, MESH : Sequence Analysis, DNA
Abstract: International audience; BACKGROUND: Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. METHODS: We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. RESULTS: Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. CONCLUSIONS: Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).
Published: 2014
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22. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella

Author: Pierre-Simon Jouk, Nicolas Thierry-Mieg, Pierre F. Ray, Karine Pernet-Gallay, Thomas Karaouzène, Denise Escalier, Charles Coutton, Christophe Arnoult, Virginie Pierre, Marie Bidart, Sylviane Hennebicq, Mariem Ben Khelifa, Raoudha Zouari, Didier Grunwald, John Rendu, Aminata Touré, Julie Delaroche, Sandra Yassine, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory ( LR11IPT05 ), Université Tunis El Manar ( UTM ) -Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), Université Joseph Fourier - Grenoble 1 ( UJF ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Genetique Chromosomique, CHU Grenoble, Clinique de Promotion des Sciences de la Reproduction - Les Jasmins ( CPSR ), Clinique de Promotion des Sciences de la Reproduction, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Institut de Biologie et de Pathologie ( DBTP ), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation ( CECOS ), Hôpital Couple Enfant de Grenoble-CHU de Grenoble, Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), This work was supported by the research grant ICG2I funded by the program GENOPAT 2009 from the French Research Agency (ANR)., ANR-09-GENO-0013,ICG2I,Identification et Caractérisation de gènes impliqués dans l'infertilité. ( 2009 ), Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université Joseph Fourier - Grenoble 1 (UJF), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Chromosomique [CHU de Grenoble], Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie et de Pathologie (DBTP), Laboratoire d’Aide à la Procréation, Département de Génétique et Procréation (CECOS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamiques Cellulaire, Tissulaire & Microscopie fonctionnelle (TIMC-IMAG-DyCTiM), ANR-09-GENO-0013,ICG2I,Identification et Caractérisation de gènes impliqués dans l'infertilité.(2009), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université Tunis El Manar (UTM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Male, MESH: Sequence Analysis, DNA, Axoneme, MESH : RNA, Messenger, [SDV]Life Sciences [q-bio], MESH: RNA Splice Sites, Male infertility, 0302 clinical medicine, MESH : Axoneme, Testis, MESH : Infertility, Male, Genetics(clinical), MESH: Genetic Variation, Genetics (clinical), Sperm motility, Primary ciliary dyskinesia, Genetics, 0303 health sciences, 030219 obstetrics & reproductive medicine, MESH: Testis, Cilium, Homozygote, MESH : Kartagener Syndrome, MESH: Sperm Motility, MESH: Axoneme, MESH : Axonemal Dyneins, Flagella, Sperm Motility, MESH: Axonemal Dyneins, MESH : Mutation, MESH : RNA Splice Sites, MESH: Homozygote, Infertility, MESH: Mutation, MESH : Male, Dynein, Flagellum, Biology, MESH: Infertility, Male, MESH: Flagella, 03 medical and health sciences, MESH : Cilia, MESH : Homozygote, MESH: Cilia, MESH : Genetic Variation, Report, medicine, Humans, Cilia, RNA, Messenger, Infertility, Male, 030304 developmental biology, MESH: RNA, Messenger, MESH : Testis, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Sperm flagellum, Kartagener Syndrome, MESH : Humans, MESH : Sperm Tail, Genetic Variation, Axonemal Dyneins, Sequence Analysis, DNA, medicine.disease, MESH: Male, MESH: Sperm Tail, MESH : Sperm Motility, Sperm Tail, Mutation, MESH: Kartagener Syndrome, RNA Splice Sites, MESH : Flagella, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH : Sequence Analysis, DNA
Abstract: International audience; Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum.
Published: 2014
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23. Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens

Author: Dorca Arévalo, Jonatan, Pauillac, Serge, Díaz Hidalgo, Laura, Martín Satué, Mireia, Popoff, Michel R., Blasi Cabús, Joan, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Universitat de Barcelona ( UB ), Bactéries anaérobies et Toxines, Institut Pasteur [Paris], This work was supported by grant SAF2011-27566 (MINECO, Spanish Government) and grant 2009 SGR 152 from AGAUR (Generalitat de Catalunya), The authors thank Inmaculada Gómez de Aranda and the CCiTUB Biology Unit of the Campus de Bellvitge for their technical assistance. We are also grateful to Dr. Mark S. McClain (Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee) for his valuable comments and discussions., Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Universitat de Barcelona (UB), Institut Pasteur [Paris] (IP), and Universitat de Barcelona
Subjects: Male, Clostridium perfringens, Toxicology, Mouse models, MESH : Green Fluorescent Proteins, Madin Darby Canine Kidney Cells, MESH: Dogs, Mice, MESH: Structure-Activity Relationship, Membrane proteins, Toxin Binding, Toxins, MESH: Animals, Kidney Tubules, Distal, lcsh:Science, MESH: Clostridium perfringens, Brain, Veterinary Diseases, Neurology, Medical Microbiology, MESH: Epithelial Cells, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Neurotoxicology, MESH : Clostridium perfringens, Cell Physiology, Multiple Sclerosis, MESH: Gene Expression, Recombinant Fusion Proteins, Primary Cell Culture, Immunology, Toxic Agents, Microbiology, Structure-Activity Relationship, MESH: Green Fluorescent Proteins, MESH: Kidney Tubules, Distal, MESH: Recombinant Fusion Proteins, MESH : Primary Cell Culture, Microbial Pathogens, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, lcsh:R, Biology and Life Sciences, Cell binding, Survival Analysis, MESH : Kidney Tubules, Distal, Cell membranes, Confocal microscopy, MESH : Gene Expression, MESH : Brain, Mutation, Clostridium Infections, MESH: Enterotoxemia, Veterinary Science, lcsh:Q, Membranes cel·lulars, Veterinary Microbiology, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, Veterinary Toxicology, Gene Expression, lcsh:Medicine, Epithelial cells, MESH: Blood-Brain Barrier, MESH : Blood-Brain Barrier, MESH : Dogs, Molecular Cell Biology, MESH : Structure-Activity Relationship, Medicine and Health Sciences, Cèl·lules epitelials, MESH : Epithelial Cells, Blood-Brain Barrier, MESH: Survival Analysis, MESH : Mutation, Research Article, MESH: Mutation, MESH : Recombinant Fusion Proteins, MESH: Biological Transport, MESH: Clostridium Infections, MESH : Male, Bacterial Toxins, Green Fluorescent Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Autoimmune Diseases, MESH: Primary Cell Culture, MESH: Brain, Dogs, MESH : Mice, Animals, MESH: Mice, MESH : Enterotoxemia, MESH : Madin Darby Canine Kidney Cells, MESH: Madin Darby Canine Kidney Cells, Biological Transport, Kidneys, Cell Biology, Demyelinating Disorders, MESH: Male, MESH : Clostridium Infections, MESH : Biological Transport, MESH: Bacterial Toxins, Membrane Trafficking, Toxines, MESH : Bacterial Toxins, Clinical Immunology, MESH : Animals, MESH : Survival Analysis, Enterotoxemia
Abstract: International audience; Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP-Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx-H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB.
Published: 2014
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24. Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice

Author: Jean-Loup Duband, Marie-France Champy, Marie-Christine Birling, Hamid Meziane, Evelyne Bloch-Gallego, Isabelle Janoueix-Lerosey, Thomas Bourgeois, Olivier Delattre, Jorge Gallego, Michel Huerre, Tania Sorg, Michel Roux, Boris Matrot, Lucille Lopez-Delisle, Estelle Durand, Cécile Pierre-Eugène, Bos, Mireille, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), PhenoPups : Preclinical Pediatric Contract Research Organization [Evry], Phenopups SAS [Evry], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie, Institut Curie [Paris], The U830 Inserm laboratory is supported bygrants from the Institut National du Cancer, the LigueNationale contre le Cancer (Equipe labellisée), theAssociation Hubert Gouin, Les Bagouz à Manon, les amisde Claire, la Fédération Enfants et Santé et la SociétéFrançaise de Lutte contre les Cancers et les Leucémiesde l’Enfant et l’Adolescent. L. L.-D. is the recipient ofa fellowship of the Ecole Polytechnique. The InstitutClinique de la Souris was funded by Inserm., Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Clinique de la Souris ( ICS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie du Développement ( LBD ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and INSTITUT CURIE
Subjects: Male, Congenital neuroblastoma, MESH : Behavior, Animal, MESH: Eating, Germline, MESH: Animals, Newborn, Feeding difficulty, brainstem, Immunoenzyme Techniques, Eating, Mice, Neuroblastoma, 0302 clinical medicine, neonatal lethality, hemic and lymphatic diseases, MESH: Behavior, Animal, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, MESH: Animals, feeding difficulties, 0303 health sciences, Behavior, Animal, plethysmography, MESH : Animals, Newborn, Respiration, 3. Good health, MESH : Phenotype, Phenotype, Oncology, 030220 oncology & carcinogenesis, Neonatal lethality, MESH: Receptor Protein-Tyrosine Kinases, MESH : Mutation, Research Paper, medicine.medical_specialty, MESH : Eating, MESH: Mutation, MESH : Male, Biology, MESH: Phenotype, 03 medical and health sciences, Germline mutation, MESH : Immunoenzyme Techniques, Internal medicine, Gene knockin, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, In patient, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Immunoenzyme Techniques, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Gynecology, MESH: Respiration, MESH: Humans, MESH : Humans, Receptor Protein-Tyrosine Kinases, MESH : Receptor Protein-Tyrosine Kinases, MESH: Neuroblastoma, MESH: Male, MESH : Respiration, Endocrinology, Animals, Newborn, ALK, MESH : Genes, Lethal, Mutation, MESH : Neuroblastoma, Genes, Lethal, MESH : Animals, MESH: Genes, Lethal
Abstract: // Lucille Lopez-Delisle 1,2 , Cecile Pierre-Eugene 1,2 , Evelyne Bloch-Gallego 3,4 , Marie-Christine Birling 5 , Jean-Loup Duband 6,7 , Estelle Durand 8 , Thomas Bourgeois 8 , Boris Matrot 8,9 , Tania Sorg 5 , Michel Huerre 10 , Hamid Meziane 5 , Michel J. Roux 5 , Marie-France Champy 5 , Jorge Gallego 9 , Olivier Delattre 1,2 , Isabelle Janoueix-Lerosey 1,2 1 Inserm U830, Paris, France; 2 Institut Curie, Centre de Recherche, Paris, France; 3 Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, France; 4 Inserm, U1016, Paris, France; 5 Institut Clinique de la Souris, Illkirch-Graffenstaden, France; 6 Sorbonne Universites, Universite Pierre et Marie Curie-Paris 6, Paris, France; 7 CNRS, Laboratoire de Biologie du Developpement, Paris, France; 8 PhenoPups SAS, Evry, France; 9 Inserm U1141, Hopital Robert Debre, Paris, France; 10 Institut Curie, Departement de Pathologie, Paris, France. Correspondence: Isabelle Janoueix-Lerosey, email: // Keywords : ALK, brainstem, neonatal lethality, plethysmography, feeding difficulties Received : March 24, 2014 Accepted : April 01, 2014 Published : April 02, 2014 Abstract The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the Alk F1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
Published: 2014
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25. Mutant cohesin in premature ovarian failure

Author: Paul A. Overbeek, Ignacio García-Tuñón, Ziva Ben-Neriah, Reiner A. Veitia, Daniel Vaiman, Elena Llano, José Luis Barbero, Marc Fellous, Sandrine Caburet, Alberto M. Pendás, Valerie A. Arboleda, Eric Vilain, Wilbur Harrison, Kazuhiro Oka, Université Paris Diderot, Ligue Nationale contre le Cancer (France), Centre National de la Recherche Scientifique (France), Institut des Maladies Rares (France), National Institutes of Health (US), University of California, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Institut Jacques Monod (IJM), Université Paris Diderot - Paris 7 (UPD7) - Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles [Los Angeles] (UCLA), Departamento de Fisiología y Farmacología, Universidad de Salamanca, Instituto de Biología Molecular y Celular del Cáncer, Department of Molecular Cellular Biology, Baylor College of Medicine, Centro de Investigaciones Biológicas (CSIC), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Department of Genetics, Hadassah University Hospital, Hadassah University Hospital, University Paris Diderot-Paris 7, Ligue Nationale contre le Cancer, Centre National de la Recherche Scientifique, GIS (Groupement d'Intérêt Scientifique), Institut des Maladies Rares, Doris Duke Charitable Foundation, National Institute of Child Health and Human Development (NICHD) (RO1HD068138 and R01HD044513), the NICHD (F31HD068136), UCLA Medical Scientist Training Program, Ministerio de Economía y Competitividad (SAF2011-25252), lentiviral mutagenesis studies were supported by the Ocular Development Fund, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Chromosomal Proteins, Non-Histone, MESH : Primary Ovarian Insufficiency, Cell Cycle Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, Primary Ovarian Insufficiency, medicine.disease_cause, Mice, 0302 clinical medicine, MESH : Cell Cycle Proteins, MESH: Animals, MESH : Female, Chromosome 7 (human), 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, MESH: Infertility, Female, Female infertility, Nuclear Proteins, General Medicine, MESH: Primary Ovarian Insufficiency, Pedigree, 3. Good health, Premature ovarian failure, Establishment of sister chromatid cohesion, medicine.anatomical_structure, Female, MESH : Mutation, Infertility, Female, MESH : Chromosomal Proteins, Non-Histone, MESH : Infertility, Female, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, Biology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Article, Frameshift mutation, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Chromosomal Proteins, Non-Histone, Internal medicine, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Cohesin, MESH : Humans, MESH : Nuclear Proteins, Oocyte, medicine.disease, MESH : Disease Models, Animal, Disease Models, Animal, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Endocrinology, MESH : Pedigree, MESH : Animals, MESH: Disease Models, Animal, MESH: Female, MESH: Nuclear Proteins
Abstract: 7 p.- 2 fig.-- et al., Premature ovarian failure is a major cause of female infertility. The genetic causes of this disorder remain unknown in most patients. Using whole-exome sequence analysis of a large consanguineous family with inherited premature ovarian failure, we identified a homozygous 1-bp deletion inducing a frameshift mutation in STAG3 on chromosome 7. STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion. Female mice devoid of Stag3 are sterile, and their fetal oocytes are arrested at early prophase I, leading to oocyte depletion at 1 week of age., Supported by grants from the University Paris Diderot-Paris 7(to Drs. Caburet, Veitia, and Fellous), the Ligue Nationale contre le Cancer and the Centre National de la Recherche Scientifique (to Drs. Caburet and Veitia), the GIS (Groupement d’Intérêt Scientifique) Institut des Maladies Rares (to Drs. Caburet and Fellous), the Doris Duke Charitable Foundation and National Institute of Child Health and Human Development (NICHD) (RO1HD068138 and R01HD044513, to Drs. Arboleda and Vilain), the NICHD (F31HD068136) and the UCLA Medical Scientist Training Program (both to Dr. Arboleda), and the Ministerio de Economía y Competitividad (SAF2011-25252) and Junta de Castilla y León (both to Drs. Llano and Pendás). The lentiviral mutagenesis studies were supported by the Ocular Development Fund (to Dr. Overbeek).
Published: 2014
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26. The cell wall pectic polymer rhamnogalacturonan-II is required for proper pollen tube elongation: implications of a putative sialyltransferase-like protein

Author: Arnaud Lehner, Marie Christine Kiefer-Meyer, Marie Dumont, Jean-Claude Mollet, Sophie Bouton, Patrice Lerouge, Aline Voxeur, Jérôme Pelloux, Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale (Glyco-MEV), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Biologie des Plantes et Innovation - UR UPJV 3900 (BIOPI), Université de Picardie Jules Verne (UPJV)-Transfrontalière BioEcoAgro - UMR 1158 (BioEcoAgro), Université d'Artois (UA)-Université de Liège-Université de Picardie Jules Verne (UPJV)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Université d'Artois (UA)-Université de Liège-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut Jean-Pierre Bourgin (IJPB), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, University of Rouen, 'Trans Channel Wallnet' project, ERDF, Biologie des Plantes et Innovation (BIOPI), Université de Picardie Jules Verne (UPJV), Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale ( Glyco-MEV ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut Jean-Pierre Bourgin ( IJPB ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, 0977 Unité associée de Biologie forestière, and Institut National de la Recherche Agronomique ( INRA )
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Arabidopsis thaliana, Polymers, [SDV]Life Sciences [q-bio], Mutant, Arabidopsis, MESH : Pollen Tube, Kdo, Plant Science, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, MESH : Arabidopsis Proteins, MESH : Arabidopsis, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Cell Wall, Gene Expression Regulation, Plant, Genes, Reporter, MESH : Pectins, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], plant cell wall, [SDV.BDD]Life Sciences [q-bio]/Development Biology, RG-II, food and beverages, MESH : Sialyltransferases, [ SDV.BV.PEP ] Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, Articles, MESH : Genes, Reporter, Dha, MESH : Phenotype, [ SDV.BV.AP ] Life Sciences [q-bio]/Vegetal Biology/Plant breeding, Phenotype, Biochemistry, Germination, Organ Specificity, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pectins, Pollen, Pollen tube, MESH : Mutation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cell wall, MESH : Organ Specificity, [ SDV.BBM.MN ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [ SDV.BDD.GAM ] Life Sciences [q-bio]/Development Biology/Gametogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, MESH : Pollen, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH : Polymers, MESH : Cell Wall, Reporter gene, Arabidopsis Proteins, MESH : Sugar Acids, pectin motif, Wild type, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], sialyltransferase-like protein, Sugar Acids, [ SDV.BIO ] Life Sciences [q-bio]/Biotechnology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biology.organism_classification, Molecular biology, pollen tube, Sialyltransferases, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, [ CHIM.POLY ] Chemical Sciences/Polymers, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, Rhamnogalacturonan-II, Mutation, MESH : Gene Expression Regulation, Plant
Abstract: International audience; BACKGROUND AND AIMSRhamnogalacturonan-II (RG-II) is one of the pectin motifs found in the cell wall of all land plants. It contains sugars such as 2-keto-3-deoxy-d-lyxo-heptulosaric acid (Dha) and 2-keto-3-deoxy-d-manno-octulosonic acid (Kdo), and within the wall RG-II is mostly found as a dimer via a borate diester cross-link. To date, little is known regarding the biosynthesis of this motif. Here, after a brief review of our current knowledge on RG-II structure, biosynthesis and function in plants, this study explores the implications of the presence of a Golgi-localized sialyltransferase-like 2 (SIA2) protein that is possibly involved in the transfer of Dha or Kdo in the RG-II of Arabidopsis thaliana pollen tubes, a fast-growing cell type used as a model for the study of cell elongation.METHODS:Two heterozygous mutant lines of arabidopsis (sia2-1+/- and qrt1 × sia2-2+/-) were investigated. sia2-2+/- was in a quartet1 background and the inserted T-DNA contained the reporter gene β-glucuronidase (GUS) under the pollen-specific promoter LAT52. Pollen germination and pollen tube phenotype and growth were analysed both in vitro and in vivo by microscopy.KEY RESULTS:Self-pollination of heterozygous lines produced no homozygous plants in the progeny, which may suggest that the mutation could be lethal. Heterozygous mutants displayed a much lower germination rate overall and exhibited a substantial delay in germination (20 h of delay to reach 30 % of pollen grain germination compared with the wild type). In both lines, mutant pollen grains that were able to produce a tube had tubes that were either bursting, abnormal (swollen or dichotomous branching tip) or much shorter compared with wild-type pollen tubes. In vivo, mutant pollen tubes were restricted to the style, whereas the wild-type pollen tubes were detected at the base of the ovary..CONCLUSIONS:This study highlights that the mutation in arabidopsis SIA2 encoding a sialyltransferase-like protein that may transfer Dha or Kdo on the RG-II motif has a dramatic effect on the stability of the pollen tube cell wall.
Published: 2014
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27. UMD (Universal Mutation Database): A generic software to build and analyze locus-specific databases

Author: Catherine Boileau, Gwenaëlle Collod-Béroud, Thierry Soussi, Christophe Béroud, Claudine Junien, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Dynamique nucléaire et plasticité du génome (DNPG), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), COLLOD-BEROUD, Gwenaëlle, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Dynamique nucléaire et plasticité du génome ( DNPG ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Databases, Factual, data analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, computer.software_genre, MDI, Software, Neoplasms, Genotype, MESH: Neoplasms, MESH: Evolution, Molecular, Genetics (clinical), Database, UMD, Chromosome Mapping, 3. Good health, MESH : Mutation, MESH : Genome, Human, MESH: Genetic Diseases, Inborn, MESH: Mutation, Human Variome Project, Locus (genetics), MESH : Databases, Factual, Biology, Evolution, Molecular, MESH : Database Management Systems, MESH : Genetic Diseases, Inborn, Genetics, Mutation database, Humans, MESH : Evolution, Molecular, Gene, MESH: Genome, Human, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genome, Human, mutation database, software, business.industry, Point mutation, MESH : Humans, Genetic Diseases, Inborn, MESH : Neoplasms, MESH: Databases, Factual, Mutation, Database Management Systems, Human genome, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Chromosome Mapping, business, computer, MESH : Chromosome Mapping, MESH: Database Management Systems
Abstract: The human genome is thought to contain about 80,000 genes and presently only 3,000 are known to be implicated in genetic diseases. In the near future, the entire sequence of the human genome will be available and the development of new methods for point mutation detection will lead to a huge increase in the identification of genes and their mutations associated with genetic diseases as well as cancers, which is growing in frequency in industrial states. The collection of these mutations will be critical for researchers and clinicians to establish genotype/phenotype correlations. Other fields such as molecular epidemiology will also be developed using these new data. Consequently, the future lies not in simple repositories of locus-specific mutations but in dynamic databases linked to various computerized tools for their analysis and that can be directly queried on-line. To meet this goal, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4(th) Dimension(R) package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data. Thanks to the flexible structure of the UMD software, it has been successfully adapted to nine genes either involved in cancer (APC, P53, RB1, MEN1, SUR1, VHL, and WT1) or in genetic diseases (FBN1 and LDLR). Four new LSDBs are under construction (VLCAD, MCAD, KIR6, and COL4A5). Finally, the data can be transferred to core databases.
Published: 2000
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28. Characterization of the SigD regulon of C. difficile and its positive control of toxin production through the regulation of tcdR

Author: Marc Monot, Johann Peltier, Martine Pestel-Caron, Jean-Louis Pons, Olga Soutourina, Imane El Meouche, Bruno Dupuy, Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes (GRAM 1.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Ecosystème intestinal, probiotiques, antibiotiques (EA 4065), Université Paris Descartes - Paris 5 (UPD5), Funding was provided by the University of Rouen., Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes ( GRAM 1.0 ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Pathogénèse des Bactéries Anaérobies, Institut Pasteur [Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Ecosystème intestinal, probiotiques, antibiotiques ( EA 4065 ), and Université Paris Descartes - Paris 5 ( UPD5 )
Subjects: MESH : Protein Biosynthesis, Transcription, Genetic, Mutant, lcsh:Medicine, MESH : Transcriptome, MESH : Promoter Regions, Genetic, MESH: Base Sequence, Transcription (biology), Sigma factor, Gene expression, MESH : Bacterial Proteins, MESH: Gene Silencing, lcsh:Science, Promoter Regions, Genetic, MESH : Clostridium difficile, MESH: Bacterial Proteins, MESH : Consensus Sequence, Regulation of gene expression, Genetics, 0303 health sciences, MESH: Gene Expression Regulation, Bacterial, MESH: Genetic Complementation Test, Multidisciplinary, MESH : Protein Binding, DNA-Directed RNA Polymerases, MESH : Phenotype, Phenotype, Flagella, MESH: Protein Biosynthesis, MESH: Transcription Initiation Site, Transcription Initiation Site, MESH : Mutation, Research Article, Protein Binding, MESH : Gene Expression Regulation, Bacterial, MESH: Mutation, Bacterial Toxins, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, MESH: Phenotype, MESH: Flagella, 03 medical and health sciences, Bacterial Proteins, MESH : DNA-Directed RNA Polymerases, Consensus Sequence, MESH : Gene Silencing, MESH: Promoter Regions, Genetic, Consensus sequence, Position-Specific Scoring Matrices, MESH: Protein Binding, Gene Silencing, MESH: Consensus Sequence, Gene, MESH: Clostridium difficile, 030304 developmental biology, Binding Sites, Base Sequence, MESH : Genetic Complementation Test, Clostridioides difficile, 030306 microbiology, MESH: Transcription, Genetic, MESH: Transcriptome, lcsh:R, Genetic Complementation Test, MESH : Transcription, Genetic, MESH: Position-Specific Scoring Matrices, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gene Expression Regulation, Bacterial, MESH : Position-Specific Scoring Matrices, MESH: DNA-Directed RNA Polymerases, Regulon, MESH: Bacterial Toxins, MESH: Binding Sites, MESH : Transcription Initiation Site, Protein Biosynthesis, Mutation, MESH : Bacterial Toxins, lcsh:Q, MESH : Base Sequence, Transcriptome, MESH : Flagella, MESH : Binding Sites
Abstract: International audience; Clostridium difficile intestinal disease is mediated largely by the actions of toxins A (TcdA) and B (TcdB), whose production occurs after the initial steps of colonization involving different surface or flagellar proteins. In B. subtilis, the sigma factor SigD controls flagellar synthesis, motility, and vegetative autolysins. A homolog of SigD encoding gene is present in the C.difficile 630 genome. We constructed a sigD mutant in C. difficile 630 ∆erm to analyze the regulon of SigD using a global transcriptomic approach. A total of 103 genes were differentially expressed between the wild-type and the sigD mutant, including genes involved in motility, metabolism and regulation. In addition, the sigD mutant displayed decreased expression of genes involved in flagellar biosynthesis, and also of genes encoding TcdA and TcdB as well as TcdR, the positive regulator of the toxins. Genomic analysis and RACE-PCR experiments allowed us to characterize promoter sequences of direct target genes of SigD including tcdR and to identify the SigD consensus. We then established that SigD positively regulates toxin expression via direct control of tcdR transcription. Interestingly, the overexpression of FlgM, a putative anti-SigD factor, inhibited the positive regulation of motility and toxin synthesis by SigD. Thus, SigD appears to be the first positive regulator of the toxin synthesis in C. difficile.
Published: 2013
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29. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Author: Raouf Ben Abdelali, Véronique Lhéritier, Jean-Yves Cahn, Françoise Huguet, Norbert Ifrah, Agnès Buzyn, Noémie de Gunzburg, Elizabeth Macintyre, Vahid Asnafi, Dominique Payet-Bornet, Sébastien Maury, Jonathan Bond, Thibaud Leguay, Amélie Trinquand, Bertrand Nadel, André Delannoy, Kheira Beldjord, Hervé Dombret, Xavier Thomas, Jérôme Lambert, Ludovic Lhermitte, Hossein Mossafa, Etienne Lengliné, Yves Chalandon, Caroline Bonmati, Aline Tanguy-Schmidt, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Cytogénétique - Pasteur-Cerba, Laboratoire Pasteur-Cerba, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Toulouse III - Paul Sabatier (UT3), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche en Cancérologie de Lyon (CRCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Ras Proteins/genetics, Oncology, Pathology, MESH : F-Box Proteins, DNA Mutational Analysis, Cell Cycle Proteins, MESH : Gene Deletion, MESH: Receptor, Notch1, 0302 clinical medicine, MESH : Cell Cycle Proteins, Receptor, Notch1, MESH: DNA Mutational Analysis, Young adult, ddc:616, 0303 health sciences, Hazard ratio, PTEN Phosphohydrolase/genetics, hemic and immune systems, 3. Good health, MESH : Phenotype, MESH: Young Adult, 030220 oncology & carcinogenesis, Predictive value of tests, Cohort, F-Box Proteins/genetics, MESH : Proto-Oncogene Proteins, MESH: Membrane Proteins, MESH: ras Proteins, medicine.medical_specialty, MESH : Young Adult, MESH : DNA Mutational Analysis, MESH: Phenotype, MESH: PTEN Phosphohydrolase, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, MESH: Cell Cycle Proteins, Humans, PTEN, Ubiquitin-Protein Ligases/genetics, MESH : Predictive Value of Tests, MESH: Kaplan-Meier Estimate, Cell Cycle Proteins/genetics, Receptor, Notch1/genetics, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Humans, Proportional hazards model, F-Box Proteins, MESH : Humans, MESH: Adult, MESH : Proportional Hazards Models, MESH: Ubiquitin-Protein Ligases, MESH : Membrane Proteins, MESH: Disease-Free Survival, Mutation, ras Proteins, Adult Acute Lymphoblastic Leukemia, MESH : Genetic Predisposition to Disease, MESH : Ubiquitin-Protein Ligases, MESH : GTP Phosphohydrolases, MESH: Female, Gene Deletion, Cancer Research, F-Box-WD Repeat-Containing Protein 7, Time Factors, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Kaplan-Meier Estimate, MESH : PTEN Phosphohydrolase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, GTP Phosphohydrolases, MESH: Proportional Hazards Models, MESH: Risk Factors, Risk Factors, hemic and lymphatic diseases, MESH : Female, biology, MESH : Receptor, Notch1, MESH: Genetic Predisposition to Disease, MESH : Adult, MESH : Risk Factors, MESH: Predictive Value of Tests, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Phenotype, MESH : Disease-Free Survival, Female, MESH : Mutation, MESH : Time Factors, Adult, MESH: Mutation, MESH: GTP Phosphohydrolases, Ubiquitin-Protein Ligases, MESH : Male, MESH: F-Box Proteins, MESH: Multivariate Analysis, MESH : Kaplan-Meier Estimate, Young Adult, Predictive Value of Tests, Proto-Oncogene Proteins, Internal medicine, medicine, Genetic Predisposition to Disease, Membrane Proteins/genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/classification/genetics/mortality/therapy, Proportional Hazards Models, 030304 developmental biology, business.industry, MESH: Time Factors, PTEN Phosphohydrolase, Membrane Proteins, MESH : Multivariate Analysis, GTP Phosphohydrolases/genetics, MESH: Male, MESH: Proto-Oncogene Proteins, Proto-Oncogene Proteins/genetics, MESH: Gene Deletion, Multivariate Analysis, biology.protein, MESH : ras Proteins, business
Abstract: Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Published: 2013
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30. Arabidopsis thaliana nicotianamine synthase 4 is required for proper response to iron deficiency and to cadmium exposure

Author: Jeremy Astier, Olivier Lamotte, Frédéric Gaymard, Emmanuel Koen, Jossia Boucherez, Angélique Besson-Bard, David Wendehenne, Pierre Richaud, Céline Duc, Antoine Gravot, Agroécologie [Dijon], Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Amélioration des Plantes et Biotechnologies Végétales (APBV), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Bioénergie et Microalgues (EBM), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche [BLAN07-2_184783], University of Burgundy (BQR project), Burgundy State (PARI AGRALE 8 project), French Ministry of Agriculture, Ministere de l'Education Nationale, de la Recherche et de la Technologie, Region Languedoc-Roussillon, Institut National de la Recherche Agronomique, Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-AGROCAMPUS OUEST, Environnement, Bioénergie, Microalgues et Plantes (EBMP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), AGROCAMPUS OUEST-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Biochimie et Physiologie Moléculaire des Plantes ( BPMP ), Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Institut national de la recherche agronomique [Montpellier] ( INRA Montpellier ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Amélioration des Plantes et Biotechnologies Végétales ( APBV ), Institut National de la Recherche Agronomique ( INRA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST, Laboratoire de Bioénergétique et Biotechnologie des Bactéries et Microalgues ( L3BM ), and Commissariat à l'énergie atomique et aux énergies alternatives ( CEA )
Subjects: 0106 biological sciences, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, MESH : Azetidinecarboxylic Acid, FMN Reductase, Arabidopsis thaliana, Mutant, Arabidopsis, Gene Expression, Plant Science, 01 natural sciences, MESH : Cation Transport Proteins, MESH : Iron, MESH : Arabidopsis Proteins, Nicotianamine synthase, MESH : Plants, Genetically Modified, chemistry.chemical_compound, MESH : Arabidopsis, Gene Expression Regulation, Plant, Gene expression, MESH: Genes, Plant, MESH : DNA, Bacterial, Homeostasis, MESH: Arabidopsis, Nicotianamine, MESH: Stress, Physiological, Cation Transport Proteins, MESH : Adaptation, Physiological, MESH : Cadmium, 2. Zero hunger, chemistry.chemical_classification, 0303 health sciences, Cadmium, MESH: Iron, biology, General Medicine, Iron Deficiencies, Plants, Genetically Modified, Adaptation, Physiological, MESH: Azetidinecarboxylic Acid, MESH : Phenotype, Phenotype, Biochemistry, MESH: Homeostasis, MESH : Homeostasis, MESH : Mutation, Azetidinecarboxylic Acid, DNA, Bacterial, MESH: Gene Expression, MESH: Mutation, Iron, MESH: Cadmium, chemistry.chemical_element, MESH: Ferritins, MESH: Arabidopsis Proteins, MESH: Alkyl and Aryl Transferases, Genes, Plant, MESH: Phenotype, 03 medical and health sciences, MESH: Cation Transport Proteins, Stress, Physiological, Iron homeostasis, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Iron deficiency (plant disorder), MESH: Gene Expression Regulation, Plant, MESH : Genes, Plant, MESH : Alkyl and Aryl Transferases, MESH : Stress, Physiological, 030304 developmental biology, MESH : FMN Reductase, Alkyl and Aryl Transferases, Arabidopsis Proteins, Iron deficiency, Nitric oxide, biology.organism_classification, MESH: Adaptation, Physiological, MESH: DNA, Bacterial, MESH : Gene Expression, Enzyme, chemistry, MESH: FMN Reductase, MESH: Plants, Genetically Modified, Ferritins, Mutation, biology.protein, MESH : Ferritins, Agronomy and Crop Science, MESH : Gene Expression Regulation, Plant, 010606 plant biology & botany
Abstract: International audience; The nicotianamine synthase (NAS) enzymes catalyze the formation of nicotianamine (NA), a non-proteinogenic amino acid involved in iron homeostasis. We undertook the functional characterization of AtNAS4, the fourth member of the Arabidopsis thaliana NAS gene family. A mutant carrying a T-DNA insertion in AtNAS4 (atnas4), as well as lines overexpressing AtNAS4 both in the atnas4 and the wild-type genetic backgrounds, were used to decipher the role of AtNAS4 in NA synthesis, iron homeostasis and the plant response to iron deficiency or cadmium supply. We showed that AtNAS4 is an important source for NA. Whereas atnas4 had normal growth in iron-sufficient medium, it displayed a reduced accumulation of ferritins and exhibited a hypersensitivity to iron deficiency. This phenotype was rescued in the complemented lines. Under iron deficiency, atnas4 displayed a lower expression of the iron uptake-related genes IRT1 and FRO2 as well as a reduced ferric reductase activity. Atnas4 plants also showed an enhanced sensitivity to cadmium while the transgenic plants overexpressing AtNAS4 were more tolerant. Collectively, our data, together with recent studies, support the hypothesis that AtNAS4 displays an important role in iron distribution and is required for proper response to iron deficiency and to cadmium supply.
Published: 2013
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31. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study

Author: Bruno Vergès, Albert Beckers, Brigitte Delemer, Vincent Rohmer, Arnaud Murat, Jean-Marc Kuhn, Philippe Ruszniewski, Christine Binquet, Julien Thevenon, Philippe Caron, Georges Weryha, Michel Rodier, Sophie Giraud, F. Archambeaud, I. Guilhem, Morgane Le Bras, Philippe Chanson, Béatrice Parfait, Jean-Louis Sadoul, Lionel Groussin, Patricia Niccoli, Catherine Cardot-Bauters, Philippe Bouchard, Eric Baudin, Françoise Duron, Michel Renard, Hélène Bihan, Véronique Kerlan, P. Lecomte, Catherine Lombard-Bohas, Abderrahmane Bourredjem, Anne Barlier, Emilie Castermans, Françoise Borson-Chazot, Bernard Goichot, Olivier Chabre, Antoine Tabarin, Alain Calender, Laurence Faivre, Hélène Du Boullay, Pierre Goudet, Eric Clauser, Alfred Penfornis, Marie-Françoise Odou, Université Joseph Fourier - Grenoble 1 ( UJF ), Immunovirologie et polymorphisme génétique, Université de Nantes ( UN ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ), Service d'Endocrinologie ( BORDEAUX - Endocrino ), CHU Bordeaux [Bordeaux], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie du Cancer et de l'Infection ( BCI - UMR S1036 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Service d'Endocrinologie ( LIEGE - Endocrino ), Université de Liège, Department of Gastroenterology, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Pathologie et virologie moléculaire ( PVM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne ( URCA ) -Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims ( CHU Reims ), Laboratoire Microorganismes : Génome et Environnement ( LMGE ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire [Rennes], Service d'Endocrinologie ( ANGERS - Endocrino ), CHU Angers, Département de Médecine Interne et Nutrition, CHU Strasbourg, Service d'Endocrinologie ( TOULOUSE - Endocrino ), CHU Toulouse [Toulouse], Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service d'Endocrinologie ( TOURS - Endocrino ), CHRU Tours, Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Conservatoire National des Arts et Métiers - Paris ( CNAM Paris ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Service d'Endocrinologie ( CHRU - Endocrino ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Diabétologie, Service des maladies métaboliques et endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Service d'Endocrinologie ( NICE - Endocrino ), CHU Nice, Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) ( PCVP / CARDIO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ), Université Joseph Fourier - Grenoble 1 (UJF), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service d'Endocrinologie (BORDEAUX - Endocrino), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie (LIEGE - Endocrino), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologie et virologie moléculaire (PVM (UMR_7151)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Service d'Endocrinologie (ANGERS - Endocrino), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Endocrinologie (TOULOUSE - Endocrino), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Endocrinologie (TOURS - Endocrino), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), Université de Nantes (UN), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, Pathologie et virologie moléculaire (PVM), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Brest (UBO), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Fédération d'endocrinologie, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
Subjects: Oncology, Male, endocrine system diseases, Proto-Oncogene Proteins c-jun, [SDV]Life Sciences [q-bio], Disease, medicine.disease_cause, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH : Female, Genetics (clinical), Mutation, General Medicine, MESH: Follow-Up Studies, MESH : Risk Factors, 3. Good health, 030220 oncology & carcinogenesis, Cohort, MESH : Proto-Oncogene Proteins, Female, MESH : Mutation, MESH : Protein Structure, Tertiary, MESH : Proto-Oncogene Proteins c-jun, MESH : Multiple Endocrine Neoplasia Type 1, Cohort study, medicine.medical_specialty, endocrine system, MESH: Mutation, Genetic counseling, MESH : Male, MESH: Multiple Endocrine Neoplasia Type 1, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Internal medicine, Proto-Oncogene Proteins, Genetics, medicine, Multiple Endocrine Neoplasia Type 1, Humans, MEN1, Family, Molecular Biology, MESH: Family, MESH: Humans, MESH: Proto-Oncogene Proteins c-jun, [ SDV ] Life Sciences [q-bio], Proportional hazards model, MESH : Humans, Cancer, MESH : Follow-Up Studies, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH: Proto-Oncogene Proteins, Cancer research, MESH : Family, MESH: Female, Follow-Up Studies
Abstract: International audience; Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.
Published: 2013
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32. The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands

Author: Didier Klug, Isabelle Denjoy, Antoine Leenhardt, Meiso Hayashi, Fabrice Extramiana, Miyuki Hayashi, Pascale Guicheney, Alice Maltret, Nathalie Roux-Buisson, Anne Messali, Philippe Maury, Jean-Marc Lupoglazoff, Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pediatrics Department, Nippon Medical School Hospital, Cardiology Department, Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], ANTE-INSERM U836, équipe 4, Muscles et pathologies, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble-CHU Grenoble, Unité de Cardiologie Néonatale, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Unité de Rythmologie et de Stimulation Cardiaque, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), French National government (PHRC no. AOR04070, P040411), Roux-Buisson, Nathalie, Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Tachycardia, Proband, Male, Pathology, Genetic testing, 030204 cardiovascular system & hematology, Ventricular tachycardia, Electrocardiography, 0302 clinical medicine, MESH : Child, Heart Rate, MESH: Child, MESH : Female, 030212 general & internal medicine, MESH: Heart Rate, Child, medicine.diagnostic_test, MESH: Adrenergic beta-Antagonists, MESH : Adult, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Ventricular Premature Complexes, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Young Adult, MESH : Electrocardiography, Catecholaminergic polymorphic ventricular tachycardia, Cardiology, Female, medicine.symptom, MESH : Mutation, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH : Male, Adrenergic beta-Antagonists, MESH : Adrenergic beta-Antagonists, MESH : Young Adult, Follow-up studies, MESH : Tachycardia, Ventricular, Asymptomatic, MESH : Syncope, Syncope, 03 medical and health sciences, Young Adult, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, MESH : Adolescent, medicine, Humans, MESH : Ventricular Premature Complexes, MESH: Adolescent, MESH: Humans, Stress test, business.industry, MESH : Heart Rate, MESH : Humans, MESH: Adult, MESH: Death, Sudden, Cardiac, medicine.disease, MESH: Male, MESH: Electrocardiography, MESH: Ventricular Premature Complexes, MESH : Exercise Test, Death, Sudden, Cardiac, Bigeminy, MESH: Syncope, Mutation, Exercise Test, Tachycardia, Ventricular, MESH: Tachycardia, Ventricular, business, MESH: Exercise Test, MESH: Female, MESH : Death, Sudden, Cardiac
Abstract: International audience; AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder with a highly malignant clinical course. Exercise-stress test is the first-line approach to diagnose suspected individuals. We sought to elucidate the value of exercise-stress test for predicting mutations and future cardiac events in CPVT-family relatives. METHODS AND RESULTS: The present study included 67 asymptomatic relatives (24 ± 15 years) of 17 genetically positive CPVT probands, who underwent exercise-stress test without any medication and genetic testing. Exercise-stress test, which was considered positive with the induction of ventricular tachycardia or premature ventricular contractions consisting of bigeminy or couplets, was positive in 17 relatives (25%). Genetic analysis disclosed mutations in 16 of these 17 relatives (94%) and in 16 of the 50 relatives (32%) with negative exercise-stress test; the sensitivity and specificity for a positive genotype were 50 and 97%, respectively (P< 0.001). Among 32 mutation carriers, cardiac events occurred in 7 of the 16 relatives with positive and 2 of the 16 relatives with negative exercise-stress test during the follow-up period of 9.6 ± 3.8 years, and four with positive and two with negative stress test were not on regular beta-blocker treatment at these events. In the 16 relatives with positive stress test, those on beta-blocker treatment demonstrated a trend of lower cardiac event rate (Log-rank P= 0.054). CONCLUSION: In asymptomatic relatives of CPVT probands, exercise-stress test can be used as a simple diagnostic tool. Nevertheless, because of the low sensitivity for predicting mutations and future cardiac events in those with negative stress test, genetic analysis should be performed to improve patient management.
Published: 2012
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33. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters

Author: Marion Travert, Jean-Philippe Jais, Olivier A. Bernard, Tak W. Mak, Rob A. Cairns, Laurence Lamant, Thérèse Rousset, Marie Parrens, Lucile Couronné, François Lemonnier, Bettina Fabiani, Laurence de Leval, Philippe Gaulard, Christian Bastard, Olivier Tournillac, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service informatique médicale et biostatistique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie et cytologie pathologiques [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Thérapie ciblée combinatoire en Onco-Hématologie (EA3846), Université d'Auvergne - Clermont-Ferrand I (UdA), Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire d'anatomie cytologie pathologiques, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Campbell Family Institute for Breast Cancer Research, University Health Network, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie Clinique, Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This study was supported in part by grants from INCa (Institut National du Cancer), ARC (Association pour la Recherche contre le Cancer), Ligue Nationale Contre le Cancer (équipe labelisée), PHRC (Programme Hospitalier de Recherche Clinique), FRM (Fondation pour la Recherche Médicale, équipe labellisée) and the Cancer Plan research Programme (Belgium, LdL). FL was a M2 student, granted from ARC and MT, a post-doctorant granted by FRM., Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Génétique des tumeurs ( U985 ), Institut Gustave Roussy ( IGR ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Toulouse III - Paul Sabatier ( UPS ), Thérapie ciblée combinatoire en Onco-Hématologie ( EA3846 ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui de Chauliac, Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Lausanne ( UNIL ) -Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ) -Institut Universitaire de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Guellaen, Georges, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]
Subjects: Male, Myeloid, MESH : Recurrence, MESH : Aged, Chromosomal translocation, MESH : T-Lymphocytes, Helper-Inducer, Biochemistry, 0302 clinical medicine, International Prognostic Index, Recurrence, MESH : Female, MESH: Aged, 0303 health sciences, Not Otherwise Specified, Hematology, T-Lymphocytes, Helper-Inducer, MESH: Lymphoma, T-Cell, Peripheral, 3. Good health, DNA-Binding Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : Proto-Oncogene Proteins, Female, MESH : DNA-Binding Proteins, MESH : Mutation, Angioimmunoblastic T-cell lymphoma, MESH: Mutation, T cell, MESH : Male, Immunology, Dioxygenases, 03 medical and health sciences, Proto-Oncogene Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Clinical significance, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: T-Lymphocytes, Helper-Inducer, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH : Lymphoma, T-Cell, Peripheral, MESH : Humans, Lymphoma, T-Cell, Peripheral, Cell Biology, medicine.disease, MESH: Male, Lymphoma, MESH: Recurrence, MESH: Proto-Oncogene Proteins, Mutation, business, MESH: Female, MESH: DNA-Binding Proteins
Abstract: Inactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (TFH) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed TFH markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.
Published: 2012
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34. Deciphering the role of GLUT4 N-glycosylation in adipocyte and muscle cell models

Author: Roland Govers, Nancy Zaarour, Yannick Le Marchand-Brustel, Marion Berenguer, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Nice-Sophia-Antipolis, Conseil Régional Provence-Alpes-Côte d'Azur, Conseil Général des Alpes Maritimes, Alfediam-Roche Diagnostics award, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nutrition, obésité et risque thrombotique ( NORT ), and Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Glycosylation, MESH : Mutant Proteins, endocrine system diseases, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, medicine.medical_treatment, MESH : Adipocytes, N-glycosylation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Myoblasts, Mice, chemistry.chemical_compound, MESH: Mutant Proteins, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Adipocyte, Adipocytes, MESH : Glucose Transporter Type 4, Myocyte, MESH: Animals, Internalization, MESH : Immunoblotting, media_common, 0303 health sciences, Glucose Transporter Type 4, biology, MESH: Immunoblotting, MESH : Glycosylation, 030302 biochemistry & molecular biology, musculoskeletal system, MESH: Glycosylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Glucose, glucose transporter 4 (GLUT4), MESH : 3T3-L1 Cells, MESH : Mutation, intracellular retention, Intracellular, hormones, hormone substitutes, and hormone antagonists, MESH : Proteolysis, MESH: Mutation, intracellular trafficking, MESH : Cell Membrane, media_common.quotation_subject, MESH: Biological Transport, Immunoblotting, MESH: Proteolysis, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, adipocyte, MESH : Myoblasts, 03 medical and health sciences, 3T3-L1 Cells, MESH : Mice, medicine, Animals, MESH: Myoblasts, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH : Glucose, Insulin, Cell Membrane, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Glucose transporter, nutritional and metabolic diseases, Biological Transport, Transporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: 3T3-L1 Cells, MESH : Biological Transport, Glucose, chemistry, Mutation, Proteolysis, biology.protein, Mutant Proteins, MESH : Animals, myoblast, MESH: Glucose Transporter Type 4, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, GLUT4, MESH: Cell Membrane
Abstract: International audience; GLUT4 (glucose transporter 4) is responsible for the insulin-induced uptake of glucose by muscle and fat cells. In non-stimulated (basal) cells, GLUT4 is retained intracellularly, whereas insulin stimulation leads to its translocation from storage compartments towards the cell surface. How GLUT4 is retained intracellularly is largely unknown. Previously, aberrant GLUT4 N-glycosylation has been linked to increased basal cell-surface levels, while N-glycosylation-deficient GLUT4 was found to be quickly degraded. As recycling and degradation of GLUT4 are positively correlated, we hypothesized that incorrect N-glycosylation of GLUT4 might reduce its intracellular retention, resulting in an increased cell-surface recycling, in increased basal cell-surface levels, and in enhanced GLUT4 degradation. In the present study, we have investigated N-glycosylation-deficient GLUT4 in detail in 3T3-L1 preadipocytes, 3T3-L1 adipocytes and L6 myoblasts. We have found no alterations in retention, insulin response, internalization or glucose transport activity. Degradation of the mutant molecule was increased, although once present at the cell surface, its degradation was identical with that of wild-type GLUT4. Our findings indicate that N-glycosylation is important for efficient trafficking of GLUT4 to its proper compartments, but once the transporter has arrived there, N-glycosylation plays no further major role in its intracellular trafficking, nor in its functional activity.
Published: 2012
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35. Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma

Author: Agata Cieslak, André Baruchel, Elizabeth Macintyre, Céline Callens, Claudine Schmitt, Anne Moreau, Patrick Villarese, Arnaud Petit, Raouf Ben Abdelali, Frederic Baleydier, Veronique Minard-Colin, Etienne Lengliné, Yves Bertrand, Anne Rullier, Vahid Asnafi, Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), CIC - Biotherapie - GHU Ouest APHP ( CIC-BT 502 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [APHP], Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Immunology, Duke University Medical Center, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Mathématiques et Applications ( LMA-Poitiers ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -CHU Saint Louis [APHP], Service d'Hématologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mathématiques et Applications (LMA-Poitiers), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Male, Cancer Research, F-Box-WD Repeat-Containing Protein 7, MESH : F-Box Proteins, Cell Cycle Proteins, MESH : Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, MESH: Calcium-Binding Proteins, MESH : Child, Preschool, medicine.disease_cause, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, MESH: Receptor, Notch1, MESH : Receptors, Antigen, T-Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Cell Cycle Proteins, MESH : Child, MESH: Child, MESH : Calcium-Binding Proteins, MESH : Female, Receptor, Notch1, Prospective cohort study, Child, Sequence Deletion, 0303 health sciences, Mutation, MESH : Prognosis, MESH : Receptor, Notch1, MESH: Receptors, Antigen, T-Cell, MESH : Infant, MESH: Sequence Deletion, Prognosis, MESH: Infant, 3. Good health, MESH: Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Female, MESH : Mutation, MESH : Apoptosis Regulatory Proteins, MESH: Mutation, Tumor suppressor gene, Adolescent, T cell, Ubiquitin-Protein Ligases, MESH : Male, Receptors, Antigen, T-Cell, MESH: F-Box Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH : Adolescent, medicine, Humans, 030304 developmental biology, MESH: Adolescent, MESH: Humans, business.industry, MESH: Apoptosis Regulatory Proteins, F-Box Proteins, MESH : Sequence Deletion, Lymphoblastic lymphoma, T-cell receptor, Calcium-Binding Proteins, MESH: Child, Preschool, MESH : Humans, Infant, medicine.disease, Minimal residual disease, MESH: Ubiquitin-Protein Ligases, MESH: Male, Clinical trial, Cancer research, MESH : Ubiquitin-Protein Ligases, business, Apoptosis Regulatory Proteins, MESH: Female
Abstract: Purpose Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/Fmut), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. Patients and Methods Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/Fmut were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRβ, and TCRδ rearrangements. Results N/Fmut were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/Fmut and identified a poor prognosis group (P = .02). On multivariate analysis of N/Fmut, TCRγ ABD, and FLASH deletion, only N/Fmut was an independent factor for good prognosis. Conclusion Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.
Published: 2012
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36. Decreased infectivity of nucleoside analogs-resistant hepatitis B virus mutants

Author: Romain Parent, Fabien Zoulim, Gaëtan Billioud, Christian Pichoud, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe 15, Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), equipe 15, Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon ( HCL ) -Hôtel-Dieu-Hospices Civils de Lyon ( HCL ) -Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL)
Subjects: Hepatitis B virus, MESH: Mutation, MESH: Virus Assembly, Viral protein, viruses, Mutant, MESH : Hepatitis B virus, MESH: Hep G2 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, Virus, MESH : Nucleosides, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Viral entry, Drug Resistance, Viral, medicine, Humans, MESH: Nucleosides, 030304 developmental biology, Infectivity, 0303 health sciences, Hepatitis B Surface Antigens, MESH: Drug Resistance, Viral, MESH: Humans, MESH : Hepatitis B Surface Antigens, Hepatology, Virus Assembly, MESH : Humans, MESH : Hep G2 Cells, virus diseases, Nucleosides, Hep G2 Cells, Virology, Molecular biology, MESH: Hepatitis B Surface Antigens, 3. Good health, MESH: Hepatitis B virus, MESH : Drug Resistance, Viral, HBeAg, Cell culture, Mutation, 030211 gastroenterology & hepatology, MESH : Mutation, MESH : Virus Assembly
Abstract: International audience; BACKGROUND & AIMS: To understand the mechanisms of emergence and selection of HBV polymerase variants, which may also harbor mutations in the overlapping envelope protein, we analyzed the in vitro virus production and infectivity of the main viral mutants resistant to lamivudine and adefovir. METHODS: HBV-resistant mutants (rtL180M+M204V, rtV173L+L180M+M204V, rtM204I, rtL180M+M204I, rtN236T, rtA181V, rtA181V+rtN236T, rtA181T+N236T, and rtA181T) were produced in HepG2 cells permanently expressing the respective viral genomes. Viral protein expression, secretion, and viral particle production were studied by ELISA, Western blot, and transmission electron microscopy. To study only the effect of surface gene mutants on virus infectivity, HepaRG cells were inoculated with HDV pseudo-particles coated with the mutant HBV envelopes. To evaluate infectivity and replication in a global fashion, HepaRG cells were inoculated with HBV mutants. RESULTS: HBeAg was expressed and secreted in cell supernatants in all mutant-expressing cell lines. As expected, mutants harboring a sW196Stop mutation in the surface gene did not express small envelope proteins. All mutants expressing HBsAg were able to produce viral particles. HDV particles coated with mutant envelopes were less infectious than WT in HepaRG cells. Finally, we found that resistant mutants exhibit lower infectivity and replication ability than WT virus. CONCLUSIONS: Based on this study, we found that envelope substitutions modulate viral protein expression, HDV coating, and viral infectivity. These envelope modifications provide novel insights into the features of emerging HBV variants during antiviral therapies and suggest that such mutants are less prone to transmission than their WT counterpart.
Published: 2012
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37. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Author: Véronique Bonnet, Hervé Crehalet, Gérald Luc, Lawrence P. Aggerbeck, Mathilde Di Filippo, Marie Elisabeth Samson-Bouma, Frédéric Gottrand, Jean-Pierre Rabès, Agnès Sassolas, Dominique Bozon, Service de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon (HCL)-Centre de Biologie et de pathologie Est, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Inflammation: mécanismes et régulation et interactions avec la nutrition et les candidoses, Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon ( HCL ) -Centre de Biologie et de pathologie Est, Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biochimie et de Génétique Moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré-GHU Paris Ile-de-France Ouest, Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale ( INSERM ), PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: dyslipidemias, familial hypocholesterolemia, chylomicrons, lipoprotein/assembly, hepatosteatosis, genetics, gene expression, genotype-phenotype correlation, splicing, TRIGLYCERIDE-TRANSFER-PROTEIN, DISULFIDE-ISOMERASE, MTP GENE, SPLICING SIGNALS, APOLIPOPROTEIN-B, IDENTIFICATION, SUBUNIT, SITE, HYPOBETALIPOPROTEINEMIA, PHENOTYPE, MESH : Abetalipoproteinemia, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Gene mutation, MESH : Child, Preschool, Compound heterozygosity, medicine.disease_cause, Biochemistry, Microsomal triglyceride transfer protein, 0302 clinical medicine, Endocrinology, Missense mutation, MESH : Female, MESH: DNA Mutational Analysis, Genetics, 0303 health sciences, Mutation, MESH: Genetic Predisposition to Disease, Abetalipoproteinemia, 3. Good health, Child, Preschool, RNA splicing, Female, MESH : Carrier Proteins, MESH : Mutation, MESH: Mutation, MESH: Carrier Proteins, QD415-436, MESH : DNA Mutational Analysis, Biology, functional analysis, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, MESH: Humans, MESH : Humans, MESH: Child, Preschool, MESH: Abetalipoproteinemia, Cell Biology, medicine.disease, Molecular biology, biology.protein, MESH : Genetic Predisposition to Disease, Carrier Proteins, Patient-Oriented and Epidemiological Research, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Minigene
Abstract: Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases.-Di Filippo, M., H. Crehalet, M. E. Samson-Bouma, V. Bonnet, L. P. Aggerbeck, J-P. Rabes, F. Gottrand, G. Luc, D. Bozon, and A. Sassolas. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. J. Lipid Res. 2012. 53: 548-555.
Published: 2012
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38. Clinical, functional and genetic analysis of twenty-four patients with chronic granulomatous disease - identification of eight novel mutations in CYBB and NCF2 genes

Author: Cécile, Martel, Michelle, Mollin, Sylvain, Beaumel, Jean Paul, Brion, Charles, Coutton, Véronique, Satre, Gaëlle, Vieville, Mary, Callanan, Christine, Lefebvre, Alexandra, Salmon, Anne, Pagnier, Dominique, Plantaz, Cécile, Bost-Bru, Laurence, Eitenschenck, Isabelle, Durieu, Daniel, Floret, Claire, Galambrun, Hervé, Chambost, Gérard, Michel, Jean-Louis, Stephan, Olivier, Hermine, Stéphane, Blanche, Nathalie, Blot, Hervé, Rubié, Guillaume, Pouessel, Stephanie, Drillon-Haus, Bernard, Conrad, Klara M, Posfay-Barbe, Zuzana, Havlicekova, Tamara, Voskresenky-Baricic, Kelecic, Jadranka, Maria Cristina, Arriazu, Luis Alberto, Garcia, Lamia, Sfaihi, Lamia Sfaihi Ben, Mansour, Pierre, Bordigoni, Marie José, Stasia, Conrad, Bernard, Posfay Barbe, Klara, Université Joseph Fourier - Grenoble 1 (UJF), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Maladie Infectieuse, CHU Grenoble, Service de Médecine Interne et Maladies Infectieuses, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service Hématologie Infantile, Service de Médecine Interne - Centre Hospitalier Lyon Sud, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Services de Réanimation et d'urgences Pédiatriques, Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie pédiatrique, CHU Saint-Etienne, Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service d'immuno-hématologie pédiatrique [CHU Necker], Service de Pédiatrie Néonatologique, CH Sallanches, Unité d'Hémato-Oncologie, Hôpital des Enfants, Service de Pédiatrie, CH de Roubaix, Service de Pédiatrie et Onco-hématologie, CHU Strasbourg, DiaGena, MCL Niederwangen, Pediatric Infectious Diseases, University Hospital of Geneva, Department of Pediatrics, Comenius University [Bratislava], Pediatric Clinic Klaiceva, University Hospital Center Zagreb, Department of Pediatric and Pneumology, Hospital Privado Comunidad Argentina, Service de pédiatrie, Hedi Chaker Hospital [Sfax], Service de Médecine Infantile II [CHRU Nancy], Université Joseph Fourier - Grenoble 1 ( UJF ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Comenius University, CHU Hédi Chaker, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Comenius University in Bratislava
Subjects: Male, MESH: Membrane Glycoproteins, MESH : Membrane Glycoproteins, MESH : Child, Preschool, Granulomatous Disease, Chronic, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Exon, 0302 clinical medicine, MESH : Child, MESH: Granulomatous Disease, Chronic, MESH: Child, Immunology and Allergy, Missense mutation, MESH : Female, MESH: NADPH Oxidase, Child, Genetics, 0303 health sciences, Mutation, Membrane Glycoproteins, ddc:618, MESH : Infant, MESH: Infant, Stop codon, 3. Good health, 030220 oncology & carcinogenesis, Child, Preschool, NADPH Oxidase 2, NADPH Oxidase/genetics, Female, MESH : Mutation, MESH: Mutation, MESH : Male, Immunology, Nonsense mutation, Biology, Frameshift mutation, 03 medical and health sciences, MESH : NADPH Oxidase, cronic granulomatous disease, genetic mutations, medicine, Humans, CYBB, 030304 developmental biology, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, MESH: Humans, Point mutation, MESH : Humans, MESH: Child, Preschool, NADPH Oxidases, Infant, Membrane Glycoproteins/genetics, Granulomatous Disease, Chronic/genetics, Molecular biology, MESH: Male, MESH : Granulomatous Disease, Chronic, MESH: Female
Abstract: International audience; Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and cannot produce superoxide anions. The most common form is caused by mutations in CYBB encoding gp91phox. We investigated 24 CGD patients and their families. Twenty-one mutations in CYBB were classified as X91(0), X91(+) or X91(-) variants according to cytochrome b (558) expression. Point mutations in encoding regions represented 50 % of the mutations found in CYBB, splice site mutations 27 %, deletions and insertions 23 %. Eight mutations in CYBB were novel leading to X91(0)CGD cases. Two of these were point mutations: c493G>T and a double mutation c625C>G in exon 6 and c1510C>T in exon 12 leading to a premature stop codon at Gly165 in gp91phox and missense mutations His209Arg/Thr503Ile respectively. Two novel splice mutations in 5'intronic regions of introns 1 and 6 were found. A novel deletion/insertion c1024_1026delCTG/insT results in a frameshift introducing a stop codon at position 346 in gp91phox. The last novel mutation was the insertion of a T at c1373 leading to a frameshift and a premature stop codon at position 484 in gp91phox. For the first time the precise size of two large mutations in CYBB was determined by array-comparative genomic hybridization and carriers' status were evaluated by multiplex ligation-dependent probe amplification assay. No clear correlation between clinical severity and CYBB mutations could be established. Of three mutations in CYBA, NCF1 and NCF2 leading to rare autosomal recessive CGD, one nonsense mutation c29G>A in exon 1 of NCF2 was new.
Published: 2012
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39. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation

Author: Sylvie Salenave, Jessica Zucman-Rossi, Emmanuelle Jeannot, Gabrielle Couchy, Philippe Chanson, Paulette Bioulac-Sage, Jean-Charles Nault, Charles Balabaud, Marie-José Redon, Camilla Pilati, Sophie Prevot, Marie-Christine Saint-Paul, Philippe Labrune, Jeanne Tran Van Nhieu, Anne de Muret, Monique Fabre, Jean-Yves Scoazec, Catherine Buffet, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pôle Digestif, Hôpital Archet 2 [Nice] (CHU), Service d'hépato-gastro-entérologie, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de Cytologie Pathologiques [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Antoine-Béclère, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie [Béclère], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anipath, UFR Médecine Lyon-RTH Laennec-UFR Médecine Lyon-RTH Laennec, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Anipath, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Hôpital Archet 2 [Nice] ( CHU ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Anipath, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre
Subjects: Male, MESH: Signal Transduction, MESH : Liver Neoplasms, MESH : GTP-Binding Protein alpha Subunits, Gs, DNA Mutational Analysis, MESH : Aged, MESH : Models, Biological, Gene mutation, MESH: Base Sequence, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : STAT3 Transcription Factor, GTP-Binding Protein alpha Subunits, Gs, MESH : Female, MESH: DNA Mutational Analysis, MESH: Carcinoma, Hepatocellular, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, MESH: STAT3 Transcription Factor, DNA, Neoplasm, MESH : Adult, Middle Aged, 3. Good health, HNF1A, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, MESH : DNA, Neoplasm, MESH : Mutation, Signal Transduction, MESH : Carcinoma, Hepatocellular, Adult, STAT3 Transcription Factor, musculoskeletal diseases, Carcinoma, Hepatocellular, MESH: Mutation, MESH: Fibrous Dysplasia, Polyostotic, MESH : Male, MESH : Fibrous Dysplasia, Polyostotic, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, Fibrous Dysplasia, Polyostotic, Models, Biological, Adenoma, Liver Cell, 03 medical and health sciences, MESH : Adenoma, Liver Cell, Chromogranins, medicine, GNAS complex locus, Humans, MESH : Middle Aged, Aged, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, Base Sequence, Hepatology, Oncogene, MESH : Humans, MESH: Models, Biological, MESH: Adult, Hepatocellular adenoma, MESH: GTP-Binding Protein alpha Subunits, Gs, medicine.disease, MESH: Male, Mutation, Inflammatory Hepatocellular Adenoma, biology.protein, Cancer research, MESH : Base Sequence, Carcinogenesis, MESH: Female
Abstract: Background & Aims Mosaic G-protein alpha-subunit ( GNAS )-activating mutations are responsible for the McCune–Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. Methods GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. Results A somatic GNAS -activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A , CTNNB1 , and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS -mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS -mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. Conclusions We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS -activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.
Published: 2012
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40. Therapeutic use of recombinant methionyl human leptin

Author: Corinne Vigouroux, Jean-François Gautier, Camille Vatier, Vigouroux, Corinne, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de diabétologie et d'endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Leptin, medicine.medical_specialty, MESH: Diabetes Mellitus, MESH: Mutation, 030209 endocrinology & metabolism, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Immune system, Insulin resistance, Weight loss, Internal medicine, medicine, Diabetes Mellitus, Animals, Humans, MESH: Obesity, Secretion, MESH: Animals, Obesity, 030304 developmental biology, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Mutation, Leptin Deficiency, MESH: Humans, MESH : Humans, digestive, oral, and skin physiology, General Medicine, MESH: Leptin, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, MESH : Diabetes Mellitus, Endocrinology, MESH : Leptin, MESH : Obesity, MESH : Animals, medicine.symptom, MESH : Mutation, Recombinant methionyl human leptin
Abstract: International audience; Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.
Published: 2012
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41. Genes involved in sex pheromone discrimination in Drosophila melanogaster and their background-dependent effect

Author: Jean-François Ferveur, Ralph J. Greenspan, Stéphane Fraichard, Benjamin Houot, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Department of Biology, West Virginia University, Kavli Institute for Brain and Mind, University of California [San Diego] (UC San Diego), University of California-University of California, This work was supported by Le Centre National de la Recherche Scientifique, the Burgundy Regional Council, the ANR (INSAVEL) to J-FF, and a National Science Foundation grant IOS-0840717 to RJG., Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), and University of California [San Diego] ( UC San Diego )
Subjects: Male, MESH: Olfactory Perception, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, MESH : Animals, Genetically Modified, lcsh:Medicine, Genes, Insect, MESH: Genes, Insect, Breeding, MESH : Behavior, Animal, MESH: Reproduction, Courtship, Animals, Genetically Modified, Sexual Behavior, Animal, 0302 clinical medicine, MESH : Drosophila melanogaster, MESH: Behavior, Animal, MESH : Female, MESH: Animals, Mating, Sex Attractants, MESH: Sexual Behavior, Animal, 10. No inequality, lcsh:Science, media_common, Genetics, 0303 health sciences, Multidisciplinary, Ecology, Behavior, Animal, Reproduction, MESH : Genes, Insect, Animal Models, MESH : Reproduction, Sensory Systems, Drosophila melanogaster, MESH: Sex Attractants, Mate choice, Sex pheromone, Alimentation et Nutrition, Female, MESH : Mutation, Research Article, MESH: Mutation, media_common.quotation_subject, MESH : Breeding, MESH : Male, MESH: Courtship, Context (language use), MESH: Breeding, Biology, MESH: Drosophila melanogaster, MESH: Animals, Genetically Modified, 03 medical and health sciences, Model Organisms, Species Specificity, MESH : Olfactory Perception, Food and Nutrition, Animals, MESH : Species Specificity, MESH: Species Specificity, Allele, MESH : Sexual Behavior, Animal, 030304 developmental biology, Evolutionary Biology, MESH : Sex Attractants, Genetically Modified, Behavior, Animal, Genes, Insect, Mutation, Olfactory Perception, Sexual Behavior, MESH : Courtship, lcsh:R, biology.organism_classification, MESH: Male, lcsh:Q, MESH : Animals, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Neuroscience
Abstract: International audience; Mate choice is based on the comparison of the sensory quality of potential mating partners, and sex pheromones play an important role in this process. In Drosophila melanogaster, contact pheromones differ between male and female in their content and in their effects on male courtship, both inhibitory and stimulatory. To investigate the genetic basis of sex pheromone discrimination, we experimentally selected males showing either a higher or lower ability to discriminate sex pheromones over 20 generations. This experimental selection was carried out in parallel on two different genetic backgrounds: wild-type and desat1 mutant, in which parental males showed high and low sex pheromone discrimination ability respectively. Male perception of male and female pheromones was separately affected during the process of selection. A comparison of transcriptomic activity between high and low discrimination lines revealed genes not only that varied according to the starting genetic background, but varied reciprocally. Mutants in two of these genes, Shaker and quick-to-court, were capable of producing similar effects on discrimination on their own, in some instances mimicking the selected lines, in others not. This suggests that discrimination of sex pheromones depends on genes whose activity is sensitive to genetic context and provides a rare, genetically defined example of the phenomenon known as "allele flips," in which interactions have reciprocal effects on different genetic backgrounds.
Published: 2012
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42. SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas

Author: Idbaih , Ahmed, Ducray , François, Dehais , Caroline, Courdy , Célia, Carpentier , Catherine, De Bernard , Simon, Uro-Coste , Emmanuelle, Mokhtari , Karima, Jouvet , Anne, Honnorat , Jérôme, Chinot , Olivier, Ramirez , Carole, Beauchesne , Patrick, Benouaich-Amiel , Alexandra, Godard , Joël, Eimer , Sandrine, PARKER , Fabrice, Lechapt-Zalcman , Emmanuelle, Colin , Philippe, Loussouarn , Delphine, Faillot , Thierry, Dam-Hieu , Phong, Elouadhani-Hamdi , Selma, Bauchet , Luc, Langlois , Olivier, Le Guerinel , Caroline, Fontaine , Denys, Vauleon , Elodie, Menei , Philippe, Fotso , Marie Janette Motsuo, Desenclos , Christine, Verrelle , Pierre, Verelle , Pierre, Ghiringhelli , François, Noel , Georges, Labrousse , François, Carpentier , Antoine, Dhermain , Frédéric, Delattre , Jean-Yves, Figarella-Branger , Dominique, Renseigné , Non, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon ( HCL ) -Hopital Neurologique, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital de Rangueil, Service de Neuropathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Laboratoire d'Histologie et de Pathologie moléculaire des tumeurs, Université Bordeaux Segalen - Bordeaux 2-EA 2406, Service de neurochirurgie [Bicêtre], Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de neurochirurgie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest ( CHU - BREST ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Études Préhistoire, Antiquité, Moyen-Age ( CEPAM ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Neurochirurgie, CHU Nice, CRLCC Eugène Marquis ( CRLCC ), CHU Angers, Micro et nanomédecines biomimétiques ( MINT ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Bretagne Loire ( UBL ), Centre Jean Perrin, CRLCC Jean Perrin, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre Paul Strauss, CRLCC Paul Strauss, Homéostasie Cellulaire et Pathologies ( HCP ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -CHU Limoges, Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Université de Limoges ( UNILIM ), Fédération Mazarin, Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy ( IGR ), Stéroides et système nerveux : physiopathologie moléculaire et clinique, and Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : Oligodendroglioma, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Male, MESH : Polymorphism, Single Nucleotide, MESH : Humans, MESH : Aged, MESH : Gene Deletion, MESH : Adult, MESH : Genes, p16, MESH : Female, MESH : Middle Aged, MESH : Mutation, MESH : Brain Neoplasms, MESH : Loss of Heterozygosity
Abstract: International audience; Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.
Published: 2012
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43. DCC constrains tumour progression via its dependence receptor activity

Author: Loraine Jarrosson-Wuilleme, Jean-Yves Scoazec, Guillaume Chazot, Marie Castets, Laura Broutier, Yann Molin, Armelle Paquet, Patrick Mehlen, Nicolas Gadot, Laetitia Mazelin, Marie Brevet, Agnès Bernet, Puisieux, Alain, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Anipath, UFR Médecine Lyon-RTH Laennec, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Deleted in Colorectal Cancer, MESH : Mutant Proteins, MESH : Receptors, Cell Surface, Apoptosis, Dependence receptor, law.invention, MESH : Adenocarcinoma, Mice, MESH: Mutant Proteins, 0302 clinical medicine, law, Netrin, MESH : Intestinal Neoplasms, MESH: Animals, MESH: Gene Silencing, Receptor, Cells, Cultured, Cancer, MESH: Receptors, Cell Surface, 0303 health sciences, MESH: Genes, APC, Multidisciplinary, MESH : Tumor Suppressor Proteins, Genomics, Netrin-1, DCC Receptor, 3. Good health, 030220 oncology & carcinogenesis, Caspases, MESH: HEK293 Cells, Disease Progression, MESH: Disease Progression, MESH : Mutation, MESH: Cells, Cultured, Genes, APC, MESH: Mutation, Context (language use), Receptors, Cell Surface, Biology, Adenocarcinoma, MESH : Nerve Growth Factors, 03 medical and health sciences, MESH : Mice, MESH : Cells, Cultured, MESH : Fibroblasts, MESH : Gene Silencing, Intestinal Neoplasms, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene silencing, Animals, Humans, MESH: Tumor Suppressor Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, Nerve Growth Factors, MESH: Intestinal Neoplasms, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Caspases, MESH: Nerve Growth Factors, Tumor Suppressor Proteins, MESH: Apoptosis, MESH : Humans, fungi, MESH: Adenocarcinoma, MESH : Disease Progression, Fibroblasts, MESH : Disease Models, Animal, MESH : HEK293 Cells, Disease Models, Animal, MESH : Genes, APC, HEK293 Cells, MESH: Fibroblasts, Immunology, Mutation, Cancer research, Suppressor, Mutant Proteins, MESH : Animals, MESH : Caspases, MESH: Disease Models, Animal, MESH : Apoptosis
Abstract: International audience; The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.
Published: 2012
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44. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy

Author: Christophe Charasse, Miguel A. Alonso, Rodrick Montjean, Dominique Pouthier, Leila Balafrej, Pierre Ronco, Jacques Dantal, Georges Deschênes, Jean-Michel Vallat, Eric LeGuern, Guillaume Canaud, Alain Bonnardeaux, Anne Guiochon-Mantel, Marie-Josèphe Tête, Olivier Gribouval, Olivia Boyer, Laurence Richard, Christelle Arrondel, Philippe Petiot, Geneviève Benoit, Odile Dubourg, Alexandre Karras, Evelyne Huynh Cong, Isabelle Broutin, Emmanuelle Plaisier, Corinne Antignac, Géraldine Mollet, Claire Pouteil-Noble, Marie-Claire Gubler, Sophie Saunier, Benoît Funalot, Patrice Deteix, Fabien Nevo, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie et Génétique Moléculaire [CHU Limoges], CHU Limoges, Centre de référence national neuropathies périphériques rares [CHU Limoges], Service de Neurologie [CHU Limoges], Service de néphrologie pédiatrique, Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], SARS International Centre for Marine Molecular Biology, Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Avenir Tour Lavoisier, Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Service de néphrologie et transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche Guy- Bernier, Hôpital Maisonneuve-Rosemont, Service de transplantation et soins intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], CH de Saint-Brieuc, Service de Néphrologie et Immunologie Clinique, Hôtel Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris Diderot - Paris 7 (UPD7), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Service de Néphrologie, Centre Hospitalier de Luxembourg [Luxembourg] (CHL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Service de Génétique Médicale [CHU Necker], Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Descartes - Paris 5 ( UPD5 ), Service de néphrologie et dialyses, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université de Montréal-CHU Sainte Justine [Montréal], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Hôtel Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Université Paris Diderot - Paris 7 ( UPD7 ), CHU Gabriel Montpied ( CHU ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ) -Hôpital de la Croix-Rousse [CHU - HCL], Centre Hospitalier de Luxembourg, Centre de Référence pour les Epilepsies Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de Référence pour les Epilepsies Rares, Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centro de Biología Molecular Severo Ochoa ( CBMSO ), Universidad Autonoma de Madrid ( UAM ) -Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ), RONCO, Pierre, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), CHU de Saint-Brieuc, Agence Nationale de la Recherche (France), Association Française contre les Myopathies, Fondation pour la Recherche Médicale, Fonds de la Recherche en Sante du Québec, and Ministerio de Ciencia e Innovación (España)
Subjects: Male, Charcot–Marie–Tooth neuropathy, Pathology, MESH : Actins, MESH : Charcot-Marie-Tooth Disease, urologic and male genital diseases, Mice, Myelin, 0302 clinical medicine, MESH : Child, Charcot-Marie-Tooth Disease, MESH: Child, MESH: Charcot-Marie-Tooth Disease, Medicine, MESH: Animals, Age of Onset, Child, 0303 health sciences, MESH: Middle Aged, Glomerulosclerosis, Focal Segmental, General Medicine, female genital diseases and pregnancy complications, MESH : Age of Onset, 3. Good health, MESH : Phenotype, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Myelin maintenance, MESH: Young Adult, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Myelin and Lymphocyte-Associated Proteolipid Proteins, MESH: Proteolipids, MESH : Heterozygote, medicine.medical_specialty, Proteolipids, MESH: Age of Onset, MESH : Young Adult, Formins, MESH: Phenotype, MESH: Actins, 03 medical and health sciences, MESH : Adolescent, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, MESH: Myelin Proteins, MESH : Middle Aged, MESH: Adolescent, MESH: Humans, MESH : Humans, Membrane Transport Proteins, Kidney metabolism, MESH: Adult, medicine.disease, MESH : Glomerulosclerosis, Focal Segmental, INF2, Endocrinology, Mutation, MESH: Schwann Cells, MESH: Female, 030217 neurology & neurosurgery, Kidney, MESH: Membrane Transport Proteins, Glomerulosclerosis, Focal segmental glomerulosclerosis, MESH : Membrane Transport Proteins, Peripheral myelin protein 22, MESH : Myelin and Lymphocyte-Associated Proteolipid Proteins, MESH : Female, MESH: Heterozygote, Myelin and Lymphocyte-Associated Proteolipid Proteins, Microfilament Proteins, Middle Aged, MESH : Adult, MESH : Kidney, Phenotype, medicine.anatomical_structure, Female, MESH : Mutation, Myelin Proteins, Adult, Heterozygote, MESH: Mutation, Adolescent, MESH : Microfilament Proteins, MESH: Glomerulosclerosis, Focal Segmental, MESH : Male, MESH : Schwann Cells, MESH : Myelin Proteins, Young Adult, MESH: Microfilament Proteins, Glomerulopathy, Internal medicine, MESH : Mice, Animals, MESH: Mice, 030304 developmental biology, urogenital system, business.industry, Myelin protein zero, MESH: Kidney, Actins, MESH: Male, MESH : Proteolipids, Schwann Cells, MESH : Animals, business
Abstract: Backgrounds: Charcot–Marie–Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot–Marie–Tooth neuropathy associated with FSGS., Methods: We performed direct genotyping of INF2 in 16 index patients with Charcot–Marie–Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted., Methods: We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot–Marie–Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2–MAL–CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42., Conclusions: INF2 mutations appear to cause many cases of FSGS-associated Charcot–Marie–Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function., Funded by the Agence Nationale de la Recherche and others.Supported by grants from the Association pour l'Utilisation du Rein Artificiel (to Dr. Antignac), Association Française contre les Myopathies (ANR-08-GENOPAT-017-01, to Dr. Antignac), Agence Nationale de la Recherche (PodoNet project number ANR-07-E-RARE-011-01 in the ERA-Net Consortium [JTC2007], to Dr. Antignac, and ANR-06-MRAR-024-01, to Dr. Leguern), Fondation pour la Recherche Médicale (project number DMP 2010-11-20-386, to Dr. Antignac, and doctoral funding, to Dr. Boyer), Association des Malades du Syndrome Néphrotique (to Dr. Mollet), Fonds de la Recherche en Santé du Québec (Fellowship Training Award to Dr. Benoit), and Ministerio de Ciencia e Innovación (BFU2009-07886 and CONSOLIDER COAT CSD2009-00016, to Dr. Alonso).
Published: 2011
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45. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

Author: Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A.-M., Caligo, M. A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S. S., Borg, A., Karlsson, P., Stenmark Askmalm, M., Barbany Bustinza, G., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Benitez, J., Hamann, U., Rookus, M. A., van den Ouweland, A. M. W., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gille, H. J. J. P., Peock, S., Frost, D., Evans, D. G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A. K., Remon, M.-A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M. C., Terry, M. B., Singer, C. F., Dressler, A.-C., Tea, M.-K., Hansen, T. V. O., Johannsson, O., Piedmonte, M., Rodriguez, G. C., Basil, J. B., Blank, S., Toland, A. E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S. A., Moysich, K. B., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O. M., Dumont, M., Greene, M., Glendon, G., Selander, T., Weerasooriya, N., Nordling, M., Bergman, A., Einbeigi, Z., Stenmark-Askmalm, M., Liedgren, S., Loman, N., Olsson, H., Kristoffersson, U., Soller, M., Jernstrom, H., Harbst, K., Henriksson, K., Lindblom, A., Arver, B., von Wachenfeldt, A., Liljegren, A., Barbany-Bustinza, G., Rantala, J., Melin, B., Gronberg, H., Stattin, E.-L., Emanuelsson, M., Ehrencrona, H., Torres, D., Rashid, M. U., Seidel-Renkert, A., Hogervorst, F. B. L., Verhoef, S., Verheus, M., van't Veer, L. J., van Leeuwen, F. E., Collee, M., Jager, A., Hooning, M. J., Tilanus-Linthorst, M. M. A., Seynaeve, C., Wijnen, J. T., Vreeswijk, M. P., Tollenaar, R. A., Ligtenberg, M. J., Hoogerbrugge, N., Ausems, M. G., van der Luijt, R. B., van Os, T. A., Gille, J. J. P., Waisfisz, Q., Meijers-Heijboer, H. E. J., Gomez-Garcia, E. B., van Roozendaal, C. E., Blok, M. J., Caanen, B., Oosterwijk, J. C., van der Hout, A. H., Mourits, M. J., Vasen, H. F., Cook, M., Platte, R., Miedzybrodzka, Z., Gregory, H., Morrison, P., Jeffers, L., Cole, T., Ong, K.-r., Hoffman, J., Donaldson, A., James, M., Downing, S., Taylor, A., Murray, A., Rogers, M. T., McCann, E., Kennedy, M. J., Barton, D., Porteous, M., Drummond, S., Brewer, C., Kivuva, E., Searle, A., Goodman, S., Hill, K., Davidson, R., Murday, V., Bradshaw, N., Snadden, L., Longmuir, M., Watt, C., Gibson, S., Haque, E., Tobias, E., Duncan, A., Jacobs, C., Langman, C., Whaite, A., Dorkins, H., Barwell, J., Chu, C., Miller, J., Ellis, I., Houghton, C., Lalloo, F., Taylor, J., Side, L., Male, A., Berlin, C., Collier, R., Douglas, F., Claber, O., Jobson, I., Walker, L., McLeod, D., Halliday, D., Durell, S., Stayner, B., Shanley, S., Rahman, N., Houlston, R., Bancroft, E., D'Mello, L., Page, E., Ardern-Jones, A., Kohut, K., Wiggins, J., Castro, E., Mitra, A., Robertson, L., Cook, J., Quarrell, O., Bardsley, C., Hodgson, S., Goff, S., Brice, G., Winchester, L., Eddy, C., Tripathi, V., Attard, V., Eccles, D., Lucassen, A., Crawford, G., McBride, D., Smalley, S., Sinilnikova, O., Leone, M., Buecher, B., Houdayer, C., Belotti, M., Tirapo, C., de Pauw, A., Bressac-de-Paillerets, B., Remenieras, A., Byrde, V., Lenoir, G., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Bourdon, V., Noguchi, T., Coulet, F., Colas, C., Soubrier, F., Coupier, I., Pujol, P., Peyrat, J.-P., Fournier, J., Revillion, F., Vennin, P., Adenis, C., Rouleau, E., Lidereau, R., Demange, L., Nogues, C., Muller, D., Fricker, J.-P., Longy, M., Sevenet, N., Toulas, C., Guimbaud, R., Gladieff, L., Feillel, V., Leroux, D., Dreyfus, H., Rebischung, C., Coron, F., Faivre, L., Prieur, F., Lebrun, M., Ferrer, S. F., Frenay, M., Venat-Bouvet, L., Mortemousque, I., Lynch, H. T., Snyder, C. L., Ejlertsen, B., Andersen, M. K., Kjaergaard, S., Senter, L., Sweet, K., O'Connor, M., Craven, C., Pharoah, P., Ramus, S., Pye, C., Harrington, P., Wozniak, E., Varon-Mateeva, R., Kast, K., Preisler-Adams, S., Deissler, H., Schonbuchner, I., Heinritz, W., Schafer, D., Aittomaki, K., Blomqvist, C., Heikkinen, T., Erkkila, R. N. I., Thorne, H., Niedermayr, E., de la Hoya, M., Perez-Segura, P., Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Department of Pediatrics, CHU Sainte Justine [Montréal], Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Queensland Institute of Medical Research, University of Delaware [Newark], Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Clinical Genetics, Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Department of Oncology, Sahlgrenska University Hospital [Gothenburg], Depts of Medicine and Biostatistics and Epidemology, Abramson Family Cancer Research Institute-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Genetic Epidemiology, Leiden University Medical Center (LUMC), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Addenbrookes Hospital, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, génétique, Institut Curie [Paris], Service de Génétique Oncologique, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Consultation d'Oncogénétique, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique oncologique (GO - UMR 8125), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre René Gauducheau, CRLCC René Gauducheau, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Internal Medicine, Huntsman Cancer Institute, Division of Special Gynecology, Medizinische Universität Wien = Medical University of Vienna-Department of OB/GYN, Dept of OB/GYN and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Faculty of Medicine, University of Iceland [Reykjavik], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Lombardi Comprehensive Cancer Center, Georgetown University, Genetic Counselling Unit, IDIBELL-Catalan Institute of Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ludwig-Maximilians-Universität München (LMU), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Heidelberg University Hospital [Heidelberg], Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), Universität Regensburg (UR), Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), Cancer Research U.K. Genetic Epidemiology Unit, Strangeways Research Laboratory, Genetic Epidemiology Unit, Department of Public Health and Primary Care, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 6, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Research Centre, CHU Ste Justine, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Génétique moléculaire, signalisation et cancer (GMSC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Human Genetics, Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Tel Aviv University (TAU), University of Pennsylvania-University of Pennsylvania, Universiteit Leiden-Universiteit Leiden, Nottingham University Hospitals NHS Trust (NUH), Roswell Park Cancer Institute [Buffalo] (RPCI), Georgetown University [Washington] (GU), Universität Leipzig, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Génétique moléculaire, signalisation et cancer ( GMSC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Cambridge [UK] ( CAM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Rigshospitalet [Copenhagen]-University of Copenhagen ( KU ), Sahlgrenska University Hospital, Abramson Family Cancer Research Institute-University of Pennsylvania School of Medicine, Deutsches Krebsforschungszentrum ( DKFZ ), INSTITUT CURIE, Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre François Baclesse, Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ), Génétique oncologique ( GO - UMR 8125 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Mount Sinai Hospital ( MSH ), Medical University of Vienna-Department of OB/GYN, Medical University of Vienna, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, Technical University of Munich ( TUM ), Ludwig-Maximilians-Universität München, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel ( CAU ), University Hospital Düsseldorf-Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Hannover Medical School [Hannover] ( MHH ), University Regensburg, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Human genetics, and CCA - Oncogenesis
Subjects: endocrine system diseases, Electrophoretic Mobility Shift Assay, MESH : Breast Neoplasms, medicine.disease_cause, Linkage Disequilibrium, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Genes, Reporter, Risk Factors, MESH: Risk Factors, Genotype, MESH : Female, Luciferases, skin and connective tissue diseases, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, Genetics, 0303 health sciences, MESH : Linkage Disequilibrium, BRCA1 Protein, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH : Genes, Reporter, MESH : Risk Factors, 3. Good health, MESH: Linkage Disequilibrium, 030220 oncology & carcinogenesis, MESH : Electrophoretic Mobility Shift Assay, Female, Breast disease, MESH : Mutation, MESH : Heterozygote, Heterozygote, MESH: Mutation, Single-nucleotide polymorphism, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, medicine, Humans, MESH : BRCA1 Protein, MESH : HeLa Cells, Genetic Predisposition to Disease, ddc:610, Allele, Molecular Biology, MESH : Haplotypes, Alleles, Genetic Association Studies, 030304 developmental biology, MESH: BRCA1 Protein, MESH : Luciferases, MESH: Humans, Hereditary cancer and cancer-related syndromes [ONCOL 1], MESH: Alleles, Haplotype, MESH : Humans, MESH: Genes, Reporter, Cancer, MESH : Genetic Association Studies, MESH: Haplotypes, medicine.disease, Haplotypes, Mutation, MESH: Electrophoretic Mobility Shift Assay, MESH: HeLa Cells, Cancer research, MESH : Genetic Predisposition to Disease, MESH: Luciferases, Carcinogenesis, MESH : Alleles, MESH: Female, MESH: Breast Neoplasms, HeLa Cells
Abstract: Item does not contain fulltext Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.
Published: 2011
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46. Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

Author: Ben Abdelali, Raouf, Asnafi, Vahid, Leguay, Thibaut, Boissel, Nicolas, Buzyn, Agnès, Chevallier, Patrice, Thomas, Xavier, Lepretre, Stephane, Huguet, Françoise, Vey, Norbert, Escoffre-Barbe, Martine, Tavernier, Emmanuelle, Reman, Oumedaly, Fegueux, Nathalie, Turlure, Pascal, Rousselot, Philippe, Cahn, Jean-Yves, Lheritier, Veronique, Chalandon, Yves, Béné, Marie-Christine, Macintyre, Elizabeth, Dombret, Hervé, Ifrah, Norbert, Renseigné, Non, Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hematology (IPC-Marseille), Service d'hématologie clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Hematology, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Edouard Herriot [CHU - HCL], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Toulouse III - Paul Sabatier ( UPS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Lapeyronie, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Cytokines, hématopoïèse et réponse immune (CHRI), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Hôpital Pontchaillou, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche en Cancérologie de Lyon (CRCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, Male, MESH : F-Box Proteins, MESH : Prospective Studies, Cell Cycle Proteins, MESH: Receptor, Notch1, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Cell Cycle Proteins, Neoplasm Proteins/genetics, MESH : Child, Clinical Protocols, MESH: Child, Mutational status, Favorable outcome, Prospective Studies, MESH: Leukemia-Lymphoma, Adult T-Cell, Receptor, Notch1, Child, ComputingMilieux_MISCELLANEOUS, MESH: Treatment Outcome, ddc:616, 0303 health sciences, Mutation, MESH : Trans-Activators, MESH: Middle Aged, Prognosis, Neoplasm Proteins, MESH: Young Adult, 030220 oncology & carcinogenesis, F-Box Proteins/genetics, Erg, medicine.medical_specialty, MESH: Gene Expression, Immunology, MESH : Young Adult, Disease-Free Survival, MESH: Prognosis, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH: Cell Cycle Proteins, MESH : Adolescent, Humans, MESH : Middle Aged, Ubiquitin-Protein Ligases/genetics, MESH : Predictive Value of Tests, MESH : Clinical Protocols, MESH: Kaplan-Meier Estimate, Cell Cycle Proteins/genetics, MESH: Adolescent, Receptor, Notch1/genetics, MESH: Humans, F-Box Proteins, MESH : Humans, MESH: Adult, Leukemia-Lymphoma, Adult T-Cell/classification/drug therapy/genetics, MESH: Ubiquitin-Protein Ligases, MESH : Leukemia-Lymphoma, Adult T-Cell, MESH : Gene Expression, MESH: Disease-Free Survival, Adult Acute Lymphoblastic Leukemia, MESH : Ubiquitin-Protein Ligases, Carcinogenesis, MESH: Female, MESH: Neoplasm Proteins, Multivariate analysis, F-Box-WD Repeat-Containing Protein 7, Gene Expression, Kaplan-Meier Estimate, medicine.disease_cause, Bioinformatics, MESH: Clinical Protocols, Leukemia-Lymphoma, Adult T-Cell, MESH : Female, BAALC, MESH : Prognosis, MESH : Receptor, Notch1, Hematology, MESH : Adult, Middle Aged, MESH: Predictive Value of Tests, Treatment Outcome, MESH : Disease-Free Survival, Female, MESH : Mutation, Adult, MESH: Mutation, Adolescent, MESH: Trans-Activators, MESH : Male, Ubiquitin-Protein Ligases, MESH: F-Box Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, Trans-Activators/genetics, MESH : Kaplan-Meier Estimate, Young Adult, Transcriptional Regulator ERG, Predictive Value of Tests, Internal medicine, medicine, 030304 developmental biology, business.industry, Cell Biology, MESH: Male, MESH: Prospective Studies, Trans-Activators, business
Abstract: Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.
Published: 2011
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47. Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains

Author: M.-A. Mazoyer, Anne Doléans-Jordheim, Emmanuelle Bergeron, F. Bereyziat, F. Morfin, S. Ben-Larbi, Jean Freney, Oana Dumitrescu, Charles Dumontet, Lars Petter Jordheim, Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Centre National de Référence des Staphylocoques, INSERM U851, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Microbiologie UNITE RTI2B, Institut des Sciences Pharmaceutiques et Biologiques ( ISPB ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon, Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Equipe 14, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon, Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie et Pathogénèse Humaine, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Oddrun Mjalands Stiftelse For Kreftforskning, Immunité infection vaccination ( I2V ), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR128-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Sequence Analysis, DNA, MESH : Escherichia coli, Time Factors, DNA Mutational Analysis, Antibiotics, Drug resistance, medicine.disease_cause, MESH : Drug Resistance, Bacterial, MESH: Drug Synergism, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Staphylococcus aureus, MESH : Bacterial Proteins, MESH: DNA Mutational Analysis, MESH : Anti-Bacterial Agents, MESH: Bacterial Proteins, MESH: Microbial Viability, 0303 health sciences, MESH: Microbial Sensitivity Tests, MESH: Escherichia coli, MESH : Amikacin, MESH : Staphylococcus aureus, Aminoglycoside, MESH: Zidovudine, Drug Synergism, General Medicine, Antimicrobial, Anti-Bacterial Agents, 3. Good health, MESH: Shigella dysenteriae, MESH : Thymidine Kinase, Infectious Diseases, MESH : Mutagens, MESH: Amikacin, Gentamicin, MESH : Mutation, Zidovudine, medicine.drug, MESH : Time Factors, Microbiology (medical), MESH: Thymidine Kinase, Staphylococcus aureus, MESH: Gentamicins, MESH: Mutation, Shigella dysenteriae, MESH : Drug Synergism, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Microbial Sensitivity Tests, MESH : DNA Mutational Analysis, Biology, Thymidine Kinase, Microbiology, 03 medical and health sciences, Bacterial Proteins, MESH: Anti-Bacterial Agents, MESH: Mutagens, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, Escherichia coli, medicine, Humans, MESH : Gentamicins, Amikacin, 030304 developmental biology, MESH : Zidovudine, [ SDE.BE ] Environmental Sciences/Biodiversity and Ecology, Microbial Viability, MESH: Humans, 030306 microbiology, MESH: Time Factors, MESH : Humans, MESH : Microbial Viability, Sequence Analysis, DNA, biochemical phenomena, metabolism, and nutrition, MESH : Shigella dysenteriae, Virology, Thymidine kinase, Mutation, MESH : Microbial Sensitivity Tests, Gentamicins, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Mutagens, MESH : Sequence Analysis, DNA
Abstract: International audience; The spread of multiresistant bacteria increases the need for new antibiotics. The observation that some nucleoside analogues have antibacterial activity led us to further investigate the antimicrobial activity and resistance of zidovudine (AZT). We determined the minimum inhibition concentration (MIC), studied time-kill curves, induced resistant bacteria and sequenced the gene for thymidine kinase. We demonstrate that AZT has a bactericidal effect on some enterobacteria. However, AZT could induce resistance in Escherichia coli. These resistances were associated with various modifications in the thymidine kinase gene. In particular, we observed the presence in this gene of an insertion sequence (IS) similar to IS911 of Shigella dysenteriae in two resistant clones. No cross-resistance with classical antibiotics in strains with modified thymidine kinase gene was observed. Finally, an additive or synergistic activity between AZT and the two aminoglycoside antibiotics amikacin and gentamicin was observed. We demonstrate the bactericidal activity of AZT and show synergy in association with gentamicin. Genetic modifications in resistant bacteria were identified. Our results indicate that AZT could potentially be added in the treatment of infections with enterobacteria or represent the basis for the development of derivatives with better activity and inducing less resistance.
Published: 2011
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48. Cracking the estrogen receptor's posttranslational code in breast tumors

Author: Laura Corbo, Jack-Michel Renoir, Coralie Poulard, Muriel Le Romancer, Stéphanie Sentis, Pascale A. Cohen, Equipe 9, Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Recepteurs et Signalisation des Interleukines ( U749 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Recepteurs et Signalisation des Interleukines (U749), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Signal Transduction, Endocrinology, Diabetes and Metabolism, Estrogen receptor, MESH : Breast Neoplasms, medicine.disease_cause, MESH: Estrogens, MESH : Ubiquitination, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Phosphorylation, 0302 clinical medicine, Endocrinology, Estrogen Receptor Modulators, MESH: Animals, MESH : Female, Phosphorylation, MESH: Estrogen Receptor alpha, MESH: Estrogen Receptor beta, 0303 health sciences, MESH : Estrogen Receptor alpha, Acetylation, MESH: Antineoplastic Agents, Hormonal, MESH: Estrogen Receptor Modulators, 3. Good health, MESH : Estrogen Receptor beta, Receptors, Estrogen, MESH : Estrogen Receptor Modulators, 030220 oncology & carcinogenesis, MESH: Receptors, Estrogen, Female, Signal transduction, MESH : Mutation, MESH: Acetylation, MESH : Antineoplastic Agents, Hormonal, Signal Transduction, MESH: Mutation, Antineoplastic Agents, Hormonal, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Biology, MESH : Acetylation, Methylation, MESH: Methylation, 03 medical and health sciences, Breast cancer, Palmitoylation, medicine, Animals, Estrogen Receptor beta, Humans, Estrogen receptor beta, 030304 developmental biology, MESH : Protein Processing, Post-Translational, MESH : Signal Transduction, MESH: Humans, MESH: Phosphorylation, MESH : Humans, Estrogen Receptor alpha, Ubiquitination, Cancer, Estrogens, MESH : Methylation, medicine.disease, Estrogen, MESH: Protein Processing, Post-Translational, Mutation, Immunology, Cancer research, MESH: Ubiquitination, MESH : Receptors, Estrogen, MESH : Estrogens, MESH : Animals, Carcinogenesis, MESH: Female, Protein Processing, Post-Translational, MESH: Breast Neoplasms
Abstract: International audience; Estrogen signaling pathways, because of their central role in regulating the growth and survival of breast tumor cells, have been identified as suitable and efficient targets for cancer therapies. Agents blocking estrogen activity are already widely used clinically, and many new molecules have entered clinical trials, but intrinsic or acquired resistance to treatment limits their efficacy. The basic molecular studies underlying estrogen signaling have defined the critical role of estrogen receptors (ER) in many aspects of breast tumorigenesis. However, important knowledge gaps remain about the role of posttranslational modifications (PTM) of ER in initiation and progression of breast carcinogenesis. Whereas major attention has been focused on the phosphorylation of ER, many other PTM (such as acetylation, ubiquitination, sumoylation, methylation, and palmitoylation) have been identified as events modifying ER expression and stability, subcellular localization, and sensitivity to hormonal response. This article will provide an overview of the current and emerging knowledge on ER PTM, with a particular focus on their deregulation in breast cancer. We also discuss their clinical relevance and the functional relationship between PTM. A thorough understanding of the complete picture of these modifications in ER carcinogenesis might not only open new avenues for identifying new markers for prognosis or prediction of response to endocrine therapy but also could promote the development of novel therapeutic strategies.
Published: 2011
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49. Complementary function and integrated wiring of the evolutionarily distinct Drosophila olfactory subsystems

Author: Raphael Rytz, Liliane Abuin, Richard Benton, Ana F. Silbering, Yael Grosjean, Gregory S.X.E. Jefferis, Pavan Ramdya, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Medical Research Council Laboratory of Molecular Biology, Centre intégratif de génomique, Université de Lausanne (UNIL), Université de Lausanne ( UNIL ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), and Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)
Subjects: MESH: Olfactory Perception, histology growth, MESH: Drosophila, receptor, Chemosensory Receptors, MESH : Animals, Genetically Modified, Ligands, Receptors, Odorant, Protein-Coupled Receptors, ligand, Animals, Genetically Modified, MESH : Maze Learning, 0302 clinical medicine, MESH : Biological Evolution, Odorant Receptors, MESH: Ligands, Drosophila Proteins, MESH: Receptors, Odorant, animal, MESH: Animals, Receptor, Antennal Lobe, 0303 health sciences, MESH : Ligands, MESH: Receptors, Ionotropic Glutamate, biology, General Neuroscience, MESH : Receptors, Ionotropic Glutamate, Articles, Olfactory Pathways, MESH : Odors, Olfactory transduction, development physiology, medicine.anatomical_structure, Local Interneurons, Drosophila, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Mutation, In-Vivo, Evolutionary Robotics, maze learning physiology, Ionotropic effect, anatomy, MESH: Mutation, odor, MESH: Drosophila Proteins, Sensory system, glutamate, MESH: Biological Evolution, biological evolution, drosophila genetic, physiology, mutation, olfactory pathway, ionotropic, odorant, Receptors, Ionotropic Glutamate, Olfactory Receptor Neurons, MESH: Animals, Genetically Modified, 03 medical and health sciences, MESH : Olfactory Perception, MESH : Receptors, Odorant, medicine, Animals, Biological Evolution, Drosophila/genetics, Drosophila Proteins/agonists, Drosophila Proteins/genetics, Maze Learning/physiology, Mutation, Odors, Olfactory Pathways/anatomy & histology, Olfactory Pathways/growth & development, Olfactory Perception/genetics, Olfactory Perception/physiology, Olfactory Receptor Neurons/anatomy & histology, Olfactory Receptor Neurons/growth & development, Receptors, Ionotropic Glutamate/agonists, Receptors, Ionotropic Glutamate/genetics, Receptors, Odorant/genetics, Receptors, Odorant/physiology, MESH : Drosophila, Maze Learning, Ionotropic Glutamate Receptors, 030304 developmental biology, Mosquito Anopheles-Gambiae, Communication, Malaria Mosquito, MESH: Odors, MESH : Olfactory Pathways, business.industry, MESH: Maze Learning, MESH: Olfactory Receptor Neurons, biology.organism_classification, Olfactory Perception, MESH : Drosophila Proteins, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Odorants, MESH : Olfactory Receptor Neurons, Antennal lobe, Neuron, MESH : Animals, business, Neuroscience, 030217 neurology & neurosurgery, Function (biology), MESH: Olfactory Pathways, Male Courtship Behavior
Abstract: author can archive publisher's version/PDF (embargo 6 months) ; 1529-2401 (Electronic ISSN); International audience; To sense myriad environmental odors, animals have evolved multiple, large families of divergent olfactory receptors. How and why distinct receptor repertoires and their associated circuits are functionally and anatomically integrated is essentially unknown. We have addressed these questions through comprehensive comparative analysis of the Drosophila olfactory subsystems that express the ionotropic receptors (IRs) and odorant receptors (ORs). We identify ligands for most IR neuron classes, revealing their specificity for select amines and acids, which complements the broader tuning of ORs for esters and alcohols. IR and OR sensory neurons exhibit glomerular convergence in segregated, although interconnected, zones of the primary olfactory center, but these circuits are extensively interdigitated in higher brain regions. Consistently, behavioral responses to odors arise from an interplay between IR- and OR-dependent pathways. We integrate knowledge on the different phylogenetic and developmental properties of these receptors and circuits to propose models for the functional contributions and evolution of these distinct olfactory subsystems.
Published: 2011
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50. Trade-off between bile resistance and nutritional competence drives Escherichia coli diversification in the mouse gut

Author: Nadine Cerf-Bensussan, Dominique Rainteau, François Taddei, Sabine Rakotobe, Marianne De Paepe, Valérie Gaboriau-Routhiau, Interactions de l'épithelium intestinal et du système immunitaire (UMR_S 793), Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Inflammation intestinale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Robustesse et évolvabilité de la vie (U1001), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), MDP was supported by the Fondation pour la Recherche Médicale (http://www.frm.org/)., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Recherche Agronomique (INRA), Interactions de l'épithelium intestinal et du système immunitaire ( UMR_S 793 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Recherche Agronomique ( INRA ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Robustesse et évolvabilité de la vie ( U1001 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Autard, Delphine
Subjects: Operon, Mutant, Genetic Fitness, MESH: Escherichia coli Proteins, Mice, MESH : Selection, Genetic, MESH: Animals, 0303 health sciences, MESH : Trans-Activators, MESH: Escherichia coli, Escherichia coli Proteins, Microbiology and Parasitology, Bacterial, SDV:GEN, MESH: Transcription Factors, MESH : Multienzyme Complexes, Microbiologie et Parasitologie, MESH : Phenotype, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Animals, Bacterial Outer Membrane Proteins, Bile Acids and Salts, Biodiversity, DNA-Binding Proteins, Escherichia coli, Flagella, Gastrointestinal Tract, Gene Expression Regulation, Immunity, Innate, Multienzyme Complexes, Mutation, Nutritional Physiological Phenomena, Phenotype, Selection, Genetic, Trans-Activators, Transcription Factors, MESH : DNA-Binding Proteins, MESH : Gene Expression Regulation, Bacterial, MESH: Phenotype, Microbiology, MESH: Flagella, MESH: Biodiversity, 03 medical and health sciences, Genetics, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Biology, Ecology, Evolution, Behavior and Systematics, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Genetic Fitness, 030306 microbiology, MESH: Bacterial Outer Membrane Proteins, Immunity, Innate, Colonisation, Regulon, MESH : Nutritional Physiological Phenomena, MESH: Gastrointestinal Tract, MESH : Gastrointestinal Tract, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Cancer Research, MESH : Escherichia coli, MESH : Transcription Factors, MESH: Selection, Genetic, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gut flora, medicine.disease_cause, MESH: Multienzyme Complexes, MESH: Genetic Fitness, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH : Biodiversity, Genetics (clinical), 2. Zero hunger, Experimental evolution, MESH: Gene Expression Regulation, Bacterial, biology, MESH : Escherichia coli Proteins, MESH : Immunity, Innate, MESH: Immunity, Innate, MESH : Mutation, Research Article, MESH: Mutation, lcsh:QH426-470, MESH: Trans-Activators, MESH: Bile Acids and Salts, Model Organisms, MESH : Mice, medicine, Selection, Genetic, MESH: Nutritional Physiological Phenomena, MESH : Bacterial Outer Membrane Proteins, MESH: Mice, 030304 developmental biology, Evolutionary Biology, Gene Expression Regulation, Bacterial, biology.organism_classification, MESH : Bile Acids and Salts, lcsh:Genetics, bacteria, MESH : Animals, MESH : Flagella, MESH: DNA-Binding Proteins
Abstract: Bacterial diversification is often observed, but underlying mechanisms are difficult to disentangle and remain generally unknown. Moreover, controlled diversification experiments in ecologically relevant environments are lacking. We studied bacterial diversification in the mammalian gut, one of the most complex bacterial environments, where usually hundreds of species and thousands of bacterial strains stably coexist. Herein we show rapid genetic diversification of an Escherichia coli strain upon colonisation of previously germ-free mice. In addition to the previously described mutations in the EnvZ/OmpR operon, we describe the rapid and systematic selection of mutations in the flagellar flhDC operon and in malT, the transcriptional activator of the maltose regulon. Moreover, within each mouse, the three mutant types coexisted at different levels after one month of colonisation. By combining in vivo studies and determination of the fitness advantages of the selected mutations in controlled in vitro experiments, we provide evidence that the selective forces that drive E. coli diversification in the mouse gut are the presence of bile salts and competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence generates sympatric diversification of the gut microbiota. These results illustrate how experimental evolution in natural environments enables identification of both the selective pressures that organisms face in their natural environment and the diversification mechanisms., Author Summary The mechanisms generating the huge biodiversity on earth are not entirely understood. Bacterial populations are powerful models to explore the mechanisms of evolution, owing to their big population size, rapid growth, and high mutation rate. One of the more complex bacterial community is the mammalian gut microbiota, and Escherichia coli is one of the first colonizers of the newborn intestine. Herein we studied diversification of an Escherichia coli strain in germ-free mice, a simplified though ecologically relevant system. We show rapid genetic diversification upon colonization, characterized by the systematic selection of mutations in three different pathways: in the global regulator EnvZ/OmpR controlling outer membrane permeability, in the flagellar operon, and in the maltose regulon. By combining in vivo and in vitro experiments, we show that the selective forces that drive E. coli diversification are the presence of bile salts and the competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence is sufficient to mediate diversification of bacteria. These results illustrate how experimental evolution in natural environments allows the identification of the selective pressures that organisms face in their natural environment, as well as the diversification mechanisms.
Published: 2011
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