Descriptor: "MESH: Introns" - Searchworks@Jio Institute Digital Library Search Results

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89 results on '"MESH: Introns"'

1. Le gène MAPT est méthylé différentiellement dans le cerveau dans la paralysie supranucléaire progressive

Author: HUIN, Vincent, Deramecourt, Vincent, Caparros-Lefebvre, Dominique, Maurage, Claude-Alain, Duyckaerts, Charles, Kovari, Eniko, Pasquier, Florence, Buée-Scherrer, Valérie, Labreuche, Julien, Behal, Hélène, Buée, Luc, Dhaenens, Claire-Marie, Sablonnière, Bernard, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, and Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, MESH: Introns, epigenomic, MESH: Alzheimer Disease / metabolism, ddc:616.89, MESH: Aged, 80 and over, MESH: DNA Methylation, Promoter Regions, Genetic, MESH: CpG Islands, Aged, 80 and over, PSP, MESH: Aged, DNA methylation, MESH: Middle Aged, mapt, Middle Aged, Frontal Lobe, Female, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Occipital Lobe, Supranuclear Palsy, Progressive, epigenetic, tau Proteins, Tissue Banks, MESH: Tissue Banks, MESH: Frontal Lobe / metabolism, MESH: Occipital Lobe / metabolism, Alzheimer Disease, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Promoter Regions, Genetic, Humans, Quantitative Biology - Genomics, Aged, Genomics (q-bio.GN), MESH: Supranuclear Palsy, Progressive / metabolism, promoter, MESH: Humans, Progressive Supranuclear Palsy, tauopathy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: tau Proteins / metabolism, Introns, MESH: Male, eye diseases, nervous system diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, FOS: Biological sciences, Quantitative Biology - Neurons and Cognition, CpG Islands, microtubule-associated protein tau, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer’s disease and Parkinson’s disease brains. However, few studies examine the sequences beyond the constitutive promoter.Objectives: Because activating different microtubule associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0.Methods: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer’s disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed.Results: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (p = 0.022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; p = 0.0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (p = 0.004), although no correlation with CpG1 methylation was observed.Conclusions: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation.
Published: 2020
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2. ATP6V1B1 recurrent mutations in Algerian deaf patients associated with renal tubular acidosis

Author: Crystel Bonnet, Sonia Talbi, Christine Petit, Fatima Ammar-Khodja, Merieme Djebbar, Farid Boudjenah, Malika Dahmani, Sofiane Ouhab, Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Établissement Public Hospitalier Bachir Mentouri, Service ORL [Tizi Ouzou], Centre Hospitalier Universitaire Mohamed Nedir, Institut de la Vision, 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), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), We are grateful to the family members for their participation in this study. The study was supported by National Veterinary School and the Algerian Ministry of Higher Education and Scientific research., Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Male, MESH: Acidosis, Renal Tubular, MESH: Introns, [SDV]Life Sciences [q-bio], Gene mutation, Gastroenterology, Renal tubular acidosis, Sensorineural hearing loss (SNHL), 0302 clinical medicine, Distal renal tubular acidosis, 030223 otorhinolaryngology, Frameshift Mutation, education.field_of_study, Enlarged vestibular aqueduct (EVA), MESH: Vestibular Aqueduct, Homozygote, MESH: Frameshift Mutation, General Medicine, Acidosis, Renal Tubular, Exons, MESH: Infant, 3. Good health, Child, Preschool, Sensorineural hearing loss, Female, MESH: Algeria, MESH: Homozygote, medicine.medical_specialty, Vacuolar Proton-Translocating ATPases, Distal renal tubular acidosis (dRTA), Hearing Loss, Sensorineural, Population, MESH: Vacuolar Proton-Translocating ATPases, Frameshift mutation, Vestibular Aqueduct, 03 medical and health sciences, 030225 pediatrics, Internal medicine, medicine, otorhinolaryngologic diseases, Humans, education, ATP6V1B1, MESH: Humans, business.industry, MESH: Child, Preschool, Infant, Metabolic acidosis, medicine.disease, Introns, MESH: Male, Otorhinolaryngology, MESH: Hearing Loss, Sensorineural, Algeria, Pediatrics, Perinatology and Child Health, business, MESH: Exons, MESH: Female, Enlarged vestibular aqueduct
Abstract: International audience; Hereditary distal renal tubular acidosis (dRTA) is a rare disorder characterized by metabolic acidosis due to impaired renal acid excretion. To date, three genes (ATP6V1B1, ATP6V0A4 and SLC4A1) have been reported to be responsible for this genetic disorder. Notably, mutations of ATP6V1B1 gene, which encode B1-subunit of H + -ATPase pump cause distal renal tubular acidosis often, associated with sensorineural hearing loss (SNHL). Furthermore, enlarged vestibular aqueduct (EVA) was also described in some patients with ATP6V1B1 mutations. Four Algerian unrelated patients presented with dRTA and SNHL were recruited. The ATP6V1B1 gene was preferentially analyzed in all these patients by Sanger sequencing. We identified two previously reported variants in ATP6V1B1 gene: a frameshift mutation (c.1155dupC: p.(Ile386Hisfs*56) in exon 12 and a splicing mutation in intron 2 (c.175-1G > C: p?). Both mutations were homozygous in affected members. Interestingly, one patient with p.(Ile386Hisfs*56) mutation presented profound SNHL and bilateral enlarged vestibular aqueduct (EVA). Our study indicates the importance contribution of ATP6V1B1 gene mutations to the pathogenesis of the dRTA in the Algerian population and will contribute to introducing principles to predict the characteristics of the dRTA in patients. Thus, screening for this gene could allow rapid patient management and provide adequate genetic counseling.
Published: 2020
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3. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author: Florian R. T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., van Rootselaar A. -F., Buratti J., Kuhnel T., Schroder C., Giesselmann S., Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., Jost B., Meyer V., Deleuze J. -F., Delpu Y., Avarello M. D. M., Vijfhuizen L. S., Rudolf G., Hirsch E., Kroes T., Reif P. S., Rosenow F., Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., Rafehi H., Steenpass L., Horsthemke B., Berkovic S. F., Bisulli F., Brancati F., Canafoglia L., Casari G., Guerrini R., Ishiura H., Licchetta L., Mei D., Pippucci T., Sadleir L., Scheffer I. E., Striano P., Tinuper P., Tsuji S., Zara F., LeGuern E., Klein K. M., Labauge P., Bennett M. F., Bahlo M., Gecz J., Corbett M. A., Tijssen M. A. J., van den Maagdenberg A. M. J. M., Depienne C., Florian, R. T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., van Rootselaar, A. -F., Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J. -F., Delpu, Y., Avarello, M. D. M., Vijfhuizen, L. S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P. S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S. F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I. E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., Leguern, E., Klein, K. M., Labauge, P., Bennett, M. F., Bahlo, M., Gecz, J., Corbett, M. A., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Depienne, C., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Amsterdam Neuroscience [Pays-Bas], Vrije Universiteit Amsterdam [Amsterdam] (VU)-University of Amsterdam [Amsterdam] (UvA)-VU University Medical Center [Amsterdam], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), 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 Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), genomic vision, Leiden University Medical Center (LUMC), Universiteit Leiden, Centre de référence des épilepsies rares [CHRU Strasbourg] (CRéER), Centre Hospitalier Régional Universitaire de Strasbourg (CHRU de Strasbourg), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, School of Biological Sciences [Adelaïde], University of Adelaide, Goethe-University Frankfurt am Main, Philipps Universität Marburg = Philipps University of Marburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Epilepsy Research Centre, University of Calgary, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), University Medical Center Groningen [Groningen] (UMCG), This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hôpitaux de Paris (APHP), INSERM, the 'Investissements d’Avenir' programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government’s Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE., We thank the families for their participation in this study, Agnès Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hôpital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Génomique Humaine (CNRGH) Institut de Biologie François Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cécile Cazeneuve (Hôpital Pitié-Salpêtrière, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions., FAME consortium : Berkovic SF, Bisulli F, Brancati F, Canafoglia L, Casari G, Guerrini R, Ishiura H, Licchetta L, Mei D, Pippucci T, Sadleir L, Scheffer IE, Striano P, Tinuper P, Tsuji S, Zara F., Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), RWTH Aachen University, Universität Duisburg-Essen [Essen], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Philipps University of Marburg, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Rahel T. Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, Anaide Lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica, Tao Ye, Damien Plassard, Bernard Jost, Vincent Meyer, Jean-François Deleuze, Yannick Delpu, Mario D.M. Avarello, Lisanne S. Vijfhuizen, Gabrielle Rudolf, Edouard Hirsch, Thessa Kroes, Philipp S. Reif, Felix Rosenow, Christos Ganos, Marie Vidailhet, Lionel Thivard, Alexandre Mathieu, Thomas Bourgeron, Ingo Kurth, Haloom Rafehi, Laura Steenpass, Bernhard Horsthemke, FAME consortium, Eric LeGuern, Karl Martin Klein, Pierre Labauge, Mark F. Bennett, Melanie Bahlo, Jozef Gecz, Mark A. Corbett, Marina A.J. Tijssen, Arn M.J.M. van den Maagdenberg, Christel Depienne, Francesca Bisulli, Laura Licchetta, Paolo Tinuper, MATHIEU, Alexandre, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Male, MESH: Introns, [SDV]Life Sciences [q-bio], Medizin, MESH: DNA Repeat Expansion, Epilepsies, Myoclonic, [SDV.GEN] Life Sciences [q-bio]/Genetics, MARCH6, expansion, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Aged, MESH: Middle Aged, DNA Repeat Expansion, Neurodegenerative diseases, MESH: Epilepsies, Myoclonic, Chromosome Mapping, Middle Aged, MESH: Epilepsies, Myoclonic/genetics, Pedigree, MESH: Young Adult, Female, ddc:500, MESH: Membrane Proteins, Technology Platforms, Genomic instability, Adult, Adolescent, MESH: Pedigree, Ubiquitin-Protein Ligases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Familial Adult Myoclonic Epilepsy type 3, Article, Young Adult, Humans, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Epilepsy, Membrane Proteins, MESH: Adult, MESH: Membrane Proteins/genetics, MESH: Ubiquitin-Protein Ligases, MESH: Male, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosome Mapping, MESH: Female, Neurological disorders
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements., Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
Published: 2019
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4. A transgenic mouse expressing CHMP2Bintron5mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia

Author: Frédérique René, Aurelia Vernay, Thiebault Lequeu, Robin Waegaert, Béatrice Blot, François Sellal, Jean-Philippe Loeffler, Rémy Sadoul, Valerie Risson, Sylvie Dirrig-Grosch, Ludivine Therreau, Laurent Schaeffer, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de 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 Mémoire Ressources et Recherche [Strasbourg] (CMRR Strasbourg), CHU Strasbourg, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Dieterle, Stéphane
Subjects: 0301 basic medicine, MESH: Introns, [SDV]Life Sciences [q-bio], MESH: Neurons, MESH: Endosomal Sorting Complexes Required for Transport, Mice, [SCCO]Cognitive science, 0302 clinical medicine, C9orf72, MESH: Behavior, Animal, ALS‐FTD, MESH: Animals, MESH: Nerve Tissue Proteins, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, Genetics (clinical), Neurons, Denervation, Behavior, Animal, Neurodegeneration, neurodegeneration, General Medicine, Anatomy, Sciatic Nerve, MESH: Gene Expression Regulation, Motor coordination, [SDV] Life Sciences [q-bio], MESH: Sciatic Nerve, medicine.anatomical_structure, Frontotemporal Dementia, Frontotemporal dementia, autophagy, MESH: Axons, MESH: Mutation, MESH: Mice, Transgenic, C9ORF72, MESH: Frontotemporal Dementia, Mice, Transgenic, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Genetics, medicine, Animals, Humans, MESH: Mice, Molecular Biology, MESH: Humans, Endosomal Sorting Complexes Required for Transport, Amyotrophic Lateral Sclerosis, [SCCO] Cognitive science, Charged multivesicular body protein 2B, medicine.disease, Spinal cord, Axons, Introns, 030104 developmental biology, Gene Expression Regulation, Mutation, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5 mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5 mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size of motor endplates and by a decrease of sciatic nerve axons area. However, spinal motor neurons cell bodies were preserved until death. In addition to the motor dysfunctions, CHMP2Bintron5 mice progressively developed FTD-relevant behavioural modifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2Bintron5 As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis and microgliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2Bintron5 in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.
Published: 2016
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5. Characterization of peptide QRFP (26RFa) and its receptor from amphioxus, Branchiostoma floridae

Author: Ingrid Lundell, Dan Larhammar, Christina Bergqvist, Görel Sundström, Jérôme Leprince, Hubert Vaudry, Bo Xu, Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Différenciation et communication neuronale et neuroendocrine (DC2N)
Subjects: MESH: Introns, Lancelet, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peptide, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Base Sequence, MESH: Neuropeptides, Receptors, G-Protein-Coupled, Endocrinology, Branchiostoma floridae, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, Cloning, Molecular, MESH: Phylogeny, Receptor, Phylogeny, MESH: Lancelets, Lancelets, chemistry.chemical_classification, biology, MESH: Peptides, Biochemistry, MESH: HEK293 Cells, Intercellular Signaling Peptides and Proteins, Evolution, Molecular Sequence Data, education, Neuropeptide, Transfection, Animals, Humans, MESH: Cloning, Molecular, G protein-coupled receptor, Amino Acid Sequence, Amphioxus, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Human evolutionary genetics, MESH: Transfection, Neuropeptides, QRFP, biology.organism_classification, Introns, HEK293 Cells, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animal Science and Zoology, Peptides
Abstract: International audience; A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3μM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.
Published: 2015
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6. Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia

Author: João Lavinha, Susana David, Liliana Antunes, Anavaj Sakuntabhai, Anabela Morais, Pedro Aguiar, Alexandra Dias, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), Universidade do Porto, Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Hospital Prof Doutor Fernando Fonseca [Amadora, Portugal], Hospital de Santa Maria [Lisboa], Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Universidade de Lisboa (ULISBOA), Universidade do Porto = University of Porto, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Universidade de Lisboa = University of Lisbon (ULISBOA)
Subjects: 0301 basic medicine, Male, Infecções Respiratórias, Genetic variants, Patologias do Glóbulo Vermelho, Genotype-to-phenotype Association, MESH: Introns, MESH: Genotype, Cohort Studies, MESH: Child, Genotype, TLR2, Child, Sickle Cellanemia, MESH: Cohort Studies, MESH: Genetic Association Studies, Genetics, Viral and Bacterial Infection, MESH: Toll-Like Receptor 2, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Sickle cell anemia, 3. Good health, Phenotype, MESH: Young Adult, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Hemolytic Component, MESH: Anemia, Sickle Cell, Determinantes Imunológicos em Doenças Crónicas, Viral and bacterial infection, Adolescent, Genetic Variants, Immunology, Anemia, Sickle Cell, Biology, MESH: Phenotype, Hemolytic component, Agentes Microbianos e Ambiente, 03 medical and health sciences, Young Adult, Fetal hemoglobin, medicine, SNP, Humans, Epidemiologia Clínica, Allele, Indel, Alleles, Genetic Association Studies, MESH: Adolescent, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], MESH: Alleles, Haplotype, MESH: Child, Preschool, MESH: Haplotypes, medicine.disease, MESH: Male, Introns, Toll-Like Receptor 2, Doenças Genéticas, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Haplotypes, Infectious disease (medical specialty), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genotype-to-phenotype association, Determinantes da Saúde e da Doença, MESH: Female
Abstract: Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) severe bacterial infection at least once during the patient's follow-up. The absence of the haplotype [Del]-T-[n ≥ 17] (Hap7) in homozygocity protected against subphenotype (B), in a statistically significant association, resisting correction for multiple testing. For the individual loci, the same association tendencies were observed as in the haplotype, including a deleterious association between the SNP rs4696480 T allele and subphenotype (A), whereas the A/A genotype was protective, and a deleterious effect of the A/T genotype with subphenotype (B), as well as including the protective effect of -196 to -174 insert (Ins) and deleterious effect of the deletion (Del) in homozygocity, against subphenotype (B). Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyurea treatment), and 3.7-kb alpha-thalassemia. Interestingly, differences between the effects of the two latter covariables favoring a reduction in the incidence rate of subphenotype (B) contrast with a resulting increase in relation to subphenotype (A). These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients This study was carried out with financial support from FCT/MEC through national funds and cofinanced by FEDER, under the Partnership Agreement PT2020, in the project with reference UIDMULTI/00211/2013, and was partially funded by FCT grants PIC/IC/83084/2007 and the Centro de Investigação em Genética Molecular Humana (CIGMH). info:eu-repo/semantics/publishedVersion
Published: 2017
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7. Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability

Author: Vincent Géli, Ana Rita Grosso, Guilhem Janbon, Emeline Coleno, Sérgio F. de Almeida, Amandine Bonnet, Adrien Presle, Sree Rama Chaitanya Sridhara, Abdessamad El-Kaoutari, Benoit Palancade, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris] (IP), This work was supported by CNRS (to B.P.), Fondation ARC pour la Recherche sur le Cancer (to B.P.), Ligue Nationale contre le Cancer (to B.P., fellowship to A.B. and Equipe Labellisée 2014 to V.G.), EMBO (short-term fellowship to A.B.), Cancéropole PACA (fellowship to A.E.), and Fundaçao para a Ciencia e Tecnologia, Portugal (PTDC/BIM-ONC/0016-2014 to S.F.d.A. and IF/00510/2014 to A.R.G.). Bioinformatic and computing support at CRCM was provided by the CRCM Integrative Bioinformatics and Datacentre IT and Scientific Computing platforms., Universidade de Lisboa (ULISBOA), Institut Pasteur [Paris], 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)-Aix Marseille Université (AMU), and Biologie des ARN des Pathogènes fongiques
Subjects: 0301 basic medicine, Transcription, Genetic, MESH: Introns, [SDV]Life Sciences [q-bio], Candida glabrata, mRNA splicing, MESH: Genotype, 0302 clinical medicine, MESH: Structure-Activity Relationship, Minor spliceosome, Gene Expression Regulation, Fungal, Databases, Genetic, DNA, Fungal, MESH: Candida glabrata, MESH: Databases, Genetic, Genetics, Splice site mutation, MESH: Genomic Instability, Nucleic Acid Heteroduplexes, genetic instability, MESH: Cryptococcus neoformans, Group II intron, R-loops, MESH: Saccharomyces cerevisiae, messenger ribonucleoparticle, Phenotype, MESH: Nucleic Acid Conformation, MESH: Schizosaccharomyces, Ribonucleoproteins, RNA splicing, MESH: Fungal Proteins, transcription, MESH: Spliceosomes, MESH: Gene Expression Regulation, Fungal, MESH: Computational Biology, Spliceosome, Genotype, intron, RNA Splicing, Saccharomyces cerevisiae, Biology, MESH: Phenotype, Genomic Instability, Cell Line, Fungal Proteins, Structure-Activity Relationship, 03 medical and health sciences, mRNP, MESH: Nucleic Acid Heteroduplexes, Schizosaccharomyces, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, MESH: DNA Damage, MESH: Humans, MESH: RNA, Fungal, MESH: Transcription, Genetic, Intron, Computational Biology, RNA, RNA, Fungal, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Introns, recombination, MESH: Cell Line, MESH: DNA, Fungal, MESH: Ribonucleoproteins, 030104 developmental biology, Cryptococcus neoformans, Spliceosomes, Nucleic Acid Conformation, MESH: RNA Splicing, 030217 neurology & neurosurgery, DNA Damage
Abstract: International audience; Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage.
Published: 2017
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8. Whole-genome analyses resolve early branches in the tree of life of modern birds

Author: Bhanu Rekepalli, Jaime Huerta-Cepas, David Haussler, Beth Shapiro, Frank E. Rheindt, Bo Li, Per Alström, Oliver A. Ryder, Salvador Capella-Gutierrez, Jianwen Li, José Alfredo Samaniego, Binghang Liu, Paula F. Campos, David P. Mindell, Xiangjiang Zhan, An Pas, Yinhua Huang, Liang Liu, Scott V. Edwards, Dave Burt, David A. Ray, Andrew Dixon, Hui Li, Toni Gabaldón, Bastien Boussau, Cai Li, Hans Ellegren, Carsten Rahbek, Shengbin Li, Michael J. Braun, Peter Houde, Peter V. Lovell, Alexandros Stamatakis, Claudia C. Weber, Yong Zhang, Jian Wang, Thomas Sicheritz-Pontén, Volodymyr Zavidovych, Alexander Suh, Xiong Yinqi, Maria Paula Cruz Schneider, Stephen J. O'Brien, Ganesh Ganapathy, Shamsuzzoha Bayzid, Huanming Yang, Guojie Zhang, Alonzo Alfaro-Núñez, Claudio V. Mello, Michael Bunce, Amy C. Driskell, Francisco Prosdocimi, Zijun Xiong, Joel Cracraft, Long Zhou, Mikkel H. Schierup, Brant C. Faircloth, Gary R. Graves, F. Keith Barker, Jon Fjeldså, Benoit Nabholz, Bent E. K. Lindow, Frederick H. Sheldon, Robb T. Brumfield, Nitish Narula, Bent O. Petersen, Kasper Munch, Klaus-Peter Koepfli, Rute R. da Fonseca, Thomas L. Bailey, Kui Wu, Quiemei Zheng, Tandy Warnow, John E. McCormack, Elizabeth P. Derryberry, Linnéa Smeds, Simon Y. W. Ho, Polina L. Perelman, Siavash Mirarab, Qi Zhou, Michael William Bruford, Knud A. Jønsson, M. Thomas P. Gilbert, Ning Li, Richard E. Green, Edward L. Braun, R. Paul Scofield, Wesley C. Warren, Zhenyu Li, Fang Zhang Zhang, Warren E. Johnson, Morgan Wirthlin, Jason T. Howard, Travis C. Glenn, Ludovic Orlando, Mads F. Bertelsen, David M. Lambert, Andre J. Aberer, Erich D. Jarvis, Sankar Subramanian, Amhed Missael Vargas Velazquez, Yongli Zeng, Eske Willerslev, Jin Xiao, Shiping Liu, Wang Jun, Howard Hughes Medical Institute (HHMI), Duke University Medical Center, University of Texas at Austin [Austin], Heidelberg Institute for Theoretical Studies (HITS ), Beijing Genomics Institute [Shenzhen] (BGI), Xi'an Jiaotong University (Xjtu), Natural History Museum of Denmark, Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), New Mexico State University, The University of Sydney, University of California, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Evolutionary Biology Centre (EBC), Uppsala University, Okinawa Institute of Science and Technology Graduate University, University of Georgia [USA], 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), Griffith University [Brisbane], Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institució Catalana de Recerca i Estudis Avançats (ICREA), Joint Institute for Computational Sciences [Knoxville] (JICS), The University of Tennessee [Knoxville], Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, Aarhus University [Aarhus], The McDonnell Genome Institute (MGI), Washington University in Saint Louis (WUSTL), Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology [Mstate, USA] (BCH-EPP), Mississippi State University [Mississippi], Department of Biological Sciences [Lubbock], Texas Tech University [Lubbock] (TTU), Department of Ecology and Evolutionary Biology [Santa Cruz], University of California [Santa Cruz] (UCSC), University of California-University of California, School of Biosciences [Cardiff], Cardiff University, Kunming Institute of Zoology, Chinese Academy of Sciences [Beijing] (CAS), International Wildlife Consultants Ltd, China Agricultural University (CAU), Tulane University, Louisiana State University (LSU), Copenhagen Zoo, Oregon Health and Science University [Portland] (OHSU), Federal University of Para - Universidade Federal do Para [Belem - Brésil], Technical University of Denmark [Lyngby] (DTU), Breeding Centre for Endangered Arabian Wildlife, Dubai Hospital, Canterbury Museum, Curtin University [Perth], Planning and Transport Research Centre (PATREC), Department of Integrative Biology [Berkeley] (IB), University of California [Berkeley], National Cancer Institute Frederick, Novosibirsk State University (NSU), Smithsonian Institution, Department of Biological Sciences [Singapore], National University of Singapore (NUS), Bell Museum of Natural History, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Department of Life Sciences, Imperial College London, Smithsonian Conservation Biology Institute, Theodosius Dobzhansky Center for Genome Bioinformatics, St Petersburg State University (SPbU), Nova Southeastern University (NSU), Center for Biomolecular Science and Engineering, San Diego Zoo Global Institute for Conservation Research, Occidental College, The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Key Laboratory of Zoological Systematics and Evolution, Chinese Academy of Agricultural Sciences (CAAS), Swedish Species Information Centre, Swedish University of Agricultural Sciences (SLU), Department of Organismic and Evolutionary Biology [Cambridge] (OEB), Harvard University [Cambridge], Institute of Theoretical Informatics, Karlsruhe Institute of Technology (KIT), Department of Biochemistry and Biophysics [San Francisco], American Museum of Natural History (AMNH), University of Florida [Gainesville] (UF), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, University of Copenhagen = Københavns Universitet (KU), King Abdulaziz University, Macau University of Science and Technology (MUST), The University of Hong Kong (HKU), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), University of California (UC), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), University of California [Santa Cruz] (UC Santa Cruz), University of California (UC)-University of California (UC), Kunming Institute of Zoology (KIZ), Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), University of California [Berkeley] (UC Berkeley), Biotechnology and Biological Sciences Research Council (BBSRC), Harvard University, and University of Copenhagen = Københavns Universitet (UCPH)
Subjects: Palaeognathae, MESH: Sequence Analysis, DNA, Genetic Speciation, MESH: Introns, Zoology, MESH: Biological Evolution, MESH: Base Sequence, Article, Coalescent theory, Avian Proteins, Birds, MESH: INDEL Mutation, INDEL Mutation, MESH: Avian Proteins, Animals, MESH: Animals, MESH: Genome, MESH: Phylogeny, Clade, Phylogeny, MESH: Genetic Speciation, Genome, Multidisciplinary, Columbea, Base Sequence, biology, Phylogenetic tree, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Sequence Analysis, DNA, Passerea, biology.organism_classification, Biological Evolution, Introns, MESH: Genes, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Genes, MESH: DNA Transposable Elements, Neognathae, MESH: Birds, DNA Transposable Elements, Neoaves
Abstract: International audience; To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
Published: 2014
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9. Association Analysis of IGF2BP2, KCNJ11, and CDKAL1 Polymorphisms with Type 2 Diabetes Mellitus in a Moroccan Population: A Case–Control Study and Meta-analysis

Author: Khaled Lasram, Malika Fakiri, Rym Kefi Ben Atig, Houda Benrahma, Redouane Boulouiz, Sonia Abdelhak, Abdelhamid Barakat, Hassan Rouba, Hicham Charoute, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), Laboratoire Agroalimentaire et Santé [Settat], Faculté des Sciences et Techniques [Settat] (FSTS), Université Hassan 1er [Settat]-Université Hassan 1er [Settat], 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), and This work was supported by NEPAD/NABNet New Partnership for Africa’s Development, North Africa Biosciences Network, and Joint WHO/EMRO-COMSTECH RAB&GH grants.
Subjects: Male, IGF2BP2 rs4402960, MESH: Introns, [SDV]Life Sciences [q-bio], MESH: tRNA Methyltransferases, Type 2 diabetes, Biochemistry, 0302 clinical medicine, MESH: Genetic Association Studies, MESH: Aged, Genetics, tRNA Methyltransferases, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: Potassium Channels, Inwardly Rectifying, RNA-Binding Proteins, Exons, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, MESH: Case-Control Studies, 3. Good health, Morocco, Female, MESH: Diabetes Mellitus, Type 2, Adult, MESH: Cyclin-Dependent Kinase 5, Population, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Diabetes mellitus, Genetic susceptibility, medicine, Humans, Genetic Predisposition to Disease, Potassium Channels, Inwardly Rectifying, education, Molecular Biology, CDKAL1, Genetic Association Studies, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, Genetic association, MESH: Humans, CDKAL1 rs7756992, Case-control study, Type 2 Diabetes Mellitus, MESH: Adult, Cyclin-Dependent Kinase 5, medicine.disease, MESH: Male, Introns, KCNJ11 rs5219, MESH: RNA-Binding Proteins, Diabetes Mellitus, Type 2, Case-Control Studies, MESH: Exons, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Associations with type 2 diabetes mellitus have been identified for variants CDKAL1 rs7756992, KCNJ11 rs5219, and IGF2BP2 rs4402960 in different populations. In a case-control study of 250 unrelated Moroccan diabetic patients and 250 healthy controls, we used TaqMan allelic discrimination assays to genotype the three SNPs and meta-analysis to investigate the association between the polymorphisms and diabetes in Arab populations. The results showed a significant diabetes association only with the variant rs4402960 of the IGF2BP2 gene under additive 2 (GG vs. TT; p = 0.009) and recessive (TT vs. GG+GT; p = 0.003) models. Meta-analysis indicated significant association between the IGF2BP2 rs4402960 and CDKAL1 rs7756992 polymorphisms and increased risk of diabetes in Arab populations. According to our results, the case-control study and meta-analysis revealed a significant association between the IGF2BP2 rs4402960 variant and type 2 diabetes in Moroccan and Arab populations.
Published: 2014
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10. The MAPT gene is differentially methylated in the progressive supranuclear palsy brain: Hypomethylation of MAPT in PSP brain

Author: HUIN, Vincent, Deramecourt, Vincent, Caparros-Lefebvre, Dominique, Maurage, Claude-Alain, Duyckaerts, Charles, Kovari, Eniko, Pasquier, Florence, Buée-Scherrer, Valérie, Labreuche, Julien, Behal, Hélène, Buée, Luc, Dhaenens, Claire-Marie, Sablonnière, Bernard, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
Subjects: MESH: Introns, MESH: Tissue Banks, MESH: Frontal Lobe / metabolism, epigenomic, MESH: Alzheimer Disease / metabolism, MESH: Aged, 80 and over, MESH: DNA Methylation, MESH: Occipital Lobe / metabolism, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Promoter Regions, Genetic, MESH: CpG Islands, PSP, MESH: Aged, MESH: Supranuclear Palsy, Progressive / metabolism, DNA methylation, promoter, MESH: Humans, MESH: Middle Aged, mapt, Progressive Supranuclear Palsy, tauopathy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: tau Proteins / metabolism, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], microtubule-associated protein tau, MESH: Female, epigenetic, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer’s disease and Parkinson’s disease brains. However, few studies examine the sequences beyond the constitutive promoter.Objectives: Because activating different microtubule associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0.Methods: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer’s disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed.Results: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (p = 0.022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; p = 0.0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (p = 0.004), although no correlation with CpG1 methylation was observed.Conclusions: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation.
Published: 2016
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11. Intron retention-dependent gene regulation in Cryptococcus neoformans

Author: Estelle Mogensen, Guilhem Janbon, Jungwook Hwang, Rony Barboux, Chung-Chau Hon, Pierre Lechat, Sara Gonzalez-Hilarion, Giovanni Bussotti, Kyung-Tae Lee, Damien Paulet, Jean Yves Coppée, Yong Sun Bahn, Caroline Proux, Frédérique Moyrand, Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris], Transcriptome et Epigénome (PF2), College of Life and Biotechnology [Séoul], Yonsei University, RIKEN Center for Life Science Technologies (RIKEN CLST), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Hanyang University, This work was supported by National Research Foundation of Korea grants (2015R1A2A1A15055687) from MEST, the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (916006-2) (to Y.S.B). This work was supported by a grant from ANR (2010-BLAN-1620-01 program YeastIntrons) to GJ. We thank Tae-Yup Kim and Anna Floyd for their technical assistance. We thank Cecelia Shertz Wall for editing the manuscript., ANR-10-BLAN-1620,YeastIntrons,Analyse globale de la régulation des ARN contenant des PTC par la voie du NMD et le complexe EJC-like chez des levures riches ou pauvres en introns(2010), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, MESH: Proteome / metabolism, MESH: Gene Expression, Proteome, RNA Stability, 030106 microbiology, MESH: Proteome / genetics, Gene Expression, MESH: Gene Expression Regulation, Fungal, MESH: Molecular Sequence Annotation, Article, Fungal Proteins, 03 medical and health sciences, MESH: Introns, Fungal genetics, Gene Expression Regulation, Fungal, Gene expression, MESH: Fungal Proteins / genetics, Gene, MESH: Cryptococcus neoformans / genetics, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Cryptococcus neoformans, Genetics, Regulation of gene expression, Fungal protein, Multidisciplinary, biology, MESH: Alternative Splicing, Alternative splicing, Intron, MESH: RNA Stability, Molecular Sequence Annotation, biology.organism_classification, Introns, Alternative Splicing, 030104 developmental biology, MESH: Genome, Fungal, MESH: Cryptococcus neoformans / metabolism, MESH: Fungal Proteins / metabolism, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome, Fungal
Abstract: The biological impact of alternative splicing is poorly understood in fungi, although recent studies have shown that these microorganisms are usually intron-rich. In this study, we re-annotated the genome of C. neoformans var. neoformans using RNA-Seq data. Comparison with C. neoformans var. grubii revealed that more than 99% of ORF-introns are in the same exact position in the two varieties whereas UTR-introns are much less evolutionary conserved. We also confirmed that alternative splicing is very common in C. neoformans, affecting nearly all expressed genes. We also observed specific regulation of alternative splicing by environmental cues in this yeast. However, alternative splicing does not appear to be an efficient method to diversify the C. neoformans proteome. Instead, our data suggest the existence of an intron retention-dependent mechanism of gene expression regulation that is not dependent on NMD. This regulatory process represents an additional layer of gene expression regulation in fungi and provides a mechanism to tune gene expression levels in response to any environmental modification.
Published: 2016
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12. Identification of three tomato flower and fruit MADS-box proteins with a putative histone deacetylase binding domain

Author: Marcel Kuntz, Joël Gaffé, Claudie Lemercier, Jean-Pierre Alcaraz, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Biochimie et biophysique des systèmes intégrés (BBSI), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Plastes et Différenciation Cellulaire (PDC), Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: 0106 biological sciences, MESH: Introns, MESH: Sequence Homology, Amino Acid, Sequence Homology, MESH: Amino Acid Sequence, MESH: Base Sequence, MESH: RNA, Plant, 01 natural sciences, Solanum lycopersicum, Genes, Reporter, MESH: Lycopersicon esculentum, MESH: Genes, Plant, MADS-box, Plant Proteins, Genetics, 0303 health sciences, Histone deacetylase 5, MESH: Plant Proteins, Histone deacetylase 2, Exons, General Medicine, Cell biology, DNA-Binding Proteins, Amino Acid, RNA, Plant, Histone deacetylase binding, MESH: DNA Primers, DNA, Plant, Molecular Sequence Data, MESH: Sequence Alignment, MADS Domain Proteins, Flowers, Biology, Genes, Plant, Histone Deacetylases, MESH: MADS Domain Proteins, 03 medical and health sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Lycopersicon esculentum, MESH: DNA, Plant, Reporter, Transcription factor, DNA Primers, 030304 developmental biology, Binding Sites, MESH: Molecular Sequence Data, Sequence Homology, Amino Acid, Base Sequence, HDAC11, HDAC10, MESH: Genes, Reporter, DNA, Plant, MESH: Flowers, HDAC4, Introns, MESH: Histone Deacetylases, Genes, MESH: Binding Sites, RNA, MESH: Exons, Sequence Alignment, MESH: DNA-Binding Proteins, 010606 plant biology & botany
Abstract: International audience; MADS-box transcription factors play crucial roles in organ and cell differentiation in organisms ranging from yeast to humans. Most of the work on plant MADS-box proteins focused on their roles in floral development whereas less information is available on their function in fruit maturation. We cloned three distinct tomato cDNAs using a RT-PCR approach, encoding LeMADS1, LeMADS5 and LeMADS6 factors and whose mRNAs mostly accumulate in tomato flowers and fruits. Phylogeny analysis indicates that LeMADS1, 5 and 6 belong to the MEF2-like family. When transiently expressed in tobacco leaves or in human cells, LeMADS1, 5 and 6 are targeted to the cell nucleus. As the endogenous target genes of these putative transcription factors are unknown, the transcriptional activity of these proteins was characterized in a heterologous system and we showed that, when fused to a Gal4-DNA-binding domain, they repress the transcription of heterologous reporter genes. Since histone deacetylases control MEF2 transcriptional activity and since a putative histone deacetylase binding site was present in LeMADS1, 5 and 6, we tested the potential interaction between these factors and HDAC5 deacetylase. Surprisingly, in this heterologous system, LeMADS1, 5 and 6 interacted with HDAC5 N-terminal region. Our data suggest that, like mammalian MEF2A, plant MADS-box transcriptional activity might be regulated by enzymes controlling chromatin acetylation.
Published: 2011
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13. Green Evolution and Dynamic Adaptations Revealed by Genomes of the Marine Picoeukaryotes Micromonas

Author: Robert Otillar, Olivier Panaud, Aaron Poliakov, Ian T. Paulsen, Eve Toulza, Steven Robbens, Heidrun Gundlach, Pedro M. Coutinho, E. Virginia Armbrust, Jill E. Gready, Klaus F. X. Mayer, Jasmyn Pangilinan, Kemin Zhou, Igor V. Grigoriev, Wenche Eikrem, Marie L. Cuvelier, Elif Demir, Ursula Goodenough, Jonathan H. Badger, Hervé Moreau, Susan Lucas, Peter von Dassow, Yves Van de Peer, Evelyne Derelle, Pierre Rouzé, Andrew E. Allen, Erika Lindquist, Uwe John, Elodie Foulon, Jeremy Schmutz, Fabrice Not, William Lanier, Meredith V. Everett, Alex N. Zelensky, Sarah M. McDonald, Benoît Piégu, Jane Grimwood, Tania Wyss, Chelle L. Gentemann, Aasf Salamov, Micaela S. Parker, Stephane Rombauts, Alexandra Z. Worden, Carolyn A. Napoli, Thomas Mock, Bernard Henrissat, Jae-Hyeok Lee, Inna Dubchak, Melinda P. Simmons, Andrea Aerts, Debashish Bhattacharya, Monterey Bay Aquarium Research Institute (MBARI), Monterey Bay Aquarium Research Institute, School of Oceanography [Seattle], University of Washington [Seattle], Center for Plant Systems Biology (PSB Center), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Department of Energy / Joint Genome Institute (DOE), Los Alamos National Laboratory (LANL), Observatoire océanologique de Banyuls (OOB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Adaptation et diversité en milieu marin (AD2M), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Architecture et fonction des macromolécules biologiques (AFMB), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Biology Institute, University of Arizona, Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Department of Plant Systems Biology, State University of Ghent, Stanford University School of Medicine [Stanford], Stanford University [Stanford], and Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, MESH: Sequence Analysis, DNA, RNA, Untranslated, MESH: Oceans and Seas, MESH: Introns, MESH: Plants, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, 01 natural sciences, Genome, 18S ribosomal RNA, Bathycoccus, MESH: Chlorophyta, MESH: RNA, Untranslated, Chlorophyta, MESH: Ecosystem, MESH: Genetic Variation, Photosynthesis, MESH: Phylogeny, Clade, Phylogeny, MESH: Photosynthesis, Plant evolution, 0303 health sciences, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Ecology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Transcription Factors, Plants, Adaptation, Physiological, Biological Evolution, MESH: Gene Expression Regulation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Genes, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Meiosis, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: DNA Transposable Elements, Oceans and Seas, Molecular Sequence Data, MESH: Biological Evolution, Genomics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GPL]Life Sciences [q-bio]/Genetics/Plants genetics, 03 medical and health sciences, Phylogenetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, MESH: Genome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 14. Life underwater, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Ecosystem, Repetitive Sequences, Nucleic Acid, 030304 developmental biology, Micromonas, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Repetitive Sequences, Nucleic Acid, MESH: Molecular Sequence Data, Genetic Variation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, biology.organism_classification, MESH: Adaptation, Physiological, Introns, MESH: Meiosis, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, Gene Expression Regulation, Genes, Phytoplankton, DNA Transposable Elements, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Transcription Factors, MESH: Phytoplankton, 010606 plant biology & botany
Abstract: Picoeukaryotes are a taxonomically diverse group of organisms less than 2 micrometers in diameter. Photosynthetic marine picoeukaryotes in the genus Micromonas thrive in ecosystems ranging from tropical to polar and could serve as sentinel organisms for biogeochemical fluxes of modern oceans during climate change. These broadly distributed primary producers belong to an anciently diverged sister clade to land plants. Although Micromonas isolates have high 18 S ribosomal RNA gene identity, we found that genomes from two isolates shared only 90% of their predicted genes. Their independent evolutionary paths were emphasized by distinct riboswitch arrangements as well as the discovery of intronic repeat elements in one isolate, and in metagenomic data, but not in other genomes. Divergence appears to have been facilitated by selection and acquisition processes that actively shape the repertoire of genes that are mutually exclusive between the two isolates differently than the core genes. Analyses of the Micromonas genomes offer valuable insights into ecological differentiation and the dynamic nature of early plant evolution.
Published: 2009
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14. C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts

Author: Jérôme Cavaillé, Marie-Line Bortolin-Cavaillé, Michel J. Weber, Marie Dance, Laboratoire de biologie moléculaire eucaryote (LBME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d'ophtalmologie [Nantes], and Hôtel-Dieu
Subjects: Ribonuclease III, MESH: Introns, Placenta, MicroRNA Gene, Gene Expression, RNA polymerase II, MESH: Base Sequence, 0302 clinical medicine, MESH: Ribonuclease III, Gene expression, MESH: Animals, MESH: Alpha-Amanitin, RNA Processing, Post-Transcriptional, Alpha-Amanitin, Genetics, 0303 health sciences, biology, MESH: Placenta, MESH: Primates, 030220 oncology & carcinogenesis, Female, RNA Polymerase II, MESH: RNA Processing, Post-Transcriptional, Primates, MESH: Cell Line, Tumor, MESH: Gene Expression, Molecular Sequence Data, Alu element, RNA polymerase III, 03 medical and health sciences, Cell Line, Tumor, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Gene, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Intron, RNA, Introns, MESH: RNA Polymerase II, MicroRNAs, biology.protein, MESH: Female, MESH: MicroRNAs
Abstract: International audience; MicroRNAs are tiny RNA molecules that play important regulatory roles in a broad range of developmental, physiological or pathological processes. Despite recent progress in our understanding of miRNA processing and biological functions, little is known about the regulatory mechanisms that control their expression at the transcriptional level. C19MC is the largest human microRNA gene cluster discovered to date. This 100-kb long cluster consists of 46 tandemly repeated, primate-specific pre-miRNA genes that are flanked by Alu elements (Alus) and embedded within a approximately 400- to 700-nt long repeated unit. It has been proposed that C19MC miRNA genes are transcribed by RNA polymerase III (Pol-III) initiating from A and B boxes embedded in upstream Alu repeats. Here, we show that C19MC miRNAs are intron-encoded and processed by the DGCR8-Drosha (Microprocessor) complex from a previously unidentified, non-protein-coding Pol-II (and not Pol-III) transcript which is mainly, if not exclusively, expressed in the placenta.
Published: 2009
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15. Recent transcontinental sweep of Toxoplasma gondii driven by a single monomorphic chromosome

Author: Blima Fux, L.D. Sibley, Asis Khan, James W. Ajioka, Benjamin M. Rosenthal, Marie-Laure Dardé, Chunlei Su, Jitender P. Dubey, Centre National de Référence (CNR) Toxoplasmose/Toxoplasma Biological Resource Center (BRC) (CNR Toxoplasmose-Toxoplasma BRC), CHU Limoges, Université de Limoges (UNILIM), Neuroépidémiologie Tropicale et Comparée (NETEC), and Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Université de Limoges (UNILIM)
Subjects: Time Factors, MESH: Introns, Range (biology), MESH: Base Sequence, MESH: Virulence, Mice, 0302 clinical medicine, Parasite hosting, MESH: Animals, MESH: Genetic Variation, MESH: Phylogeny, Phylogeny, MESH: Evolution, Molecular, Recombination, Genetic, Genetics, 0303 health sciences, education.field_of_study, MESH: Toxoplasmosis, Animal, Multidisciplinary, Virulence, Phylogenetic tree, MESH: Polymorphism, Single Nucleotide, MESH: Toxoplasma, Biological Sciences, MESH: Crosses, Genetic, Europe, MESH: Recombination, Genetic, Toxoplasma, Molecular Sequence Data, 030231 tropical medicine, Population, MESH: Genetics, Population, Biology, Models, Biological, Polymorphism, Single Nucleotide, Chromosomes, Evolution, Molecular, 03 medical and health sciences, Phylogenetics, Genetic variation, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, education, MESH: Mice, Alleles, Crosses, Genetic, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, MESH: Alleles, MESH: Time Factors, Haplotype, MESH: Models, Biological, Genetic Variation, Toxoplasma gondii, MESH: Haplotypes, biology.organism_classification, Introns, MESH: North America, Genetics, Population, Toxoplasmosis, Animal, Haplotypes, Evolutionary biology, North America, MESH: Chromosomes, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe
Abstract: Toxoplasma gondii is a highly prevalent protozoan parasite that infects a wide range of animals and threatens human health by contaminating food and water. A markedly limited number of clonal parasite lineages have been recognized as predominating in North American and European populations, whereas strains from South America are comparatively diverse. Here, we show that strains from North America and Europe share distinct genetic polymorphisms that are mutually exclusive from polymorphisms in strains from the south. A striking exception to this geographic segregation is a monomorphic version of one chromosome (Chr1a) that characterizes virtually all northern and many southern isolates. Using a combination of molecular phylogenetic and phenotypic analyses, we conclude that northern and southern parasite populations diverged from a common ancestor in isolation over a period of ≈10 6 yr, and that the monomorphic Chr1a has swept each population within the past 10,000 years. Like its definitive feline hosts, T. gondii may have entered South America and diversified there after reestablishment of the Panamanian land bridge. Since then, recombination has been an infrequent but important force in generating new T. gondii genotypes. Genes unique to a monomorphic version of a single parasite chromosome may have facilitated a recent population sweep of a limited number of highly successful T. gondii lineages.
Published: 2007
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16. Nuclear pore components affect distinct stages of intron-containing gene expression

Author: Bonnet, Amandine, Bretes, Hugo, Palancade, Benoit, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Gènes Génomes Cellules, Université Paris-Sud - Paris 11 (UP11), CNRS, Fondation ARC pour la Recherche sur le Cancer [Projet ARC), Ligue Nationale contre le Cancer [Comité d'Ile de France), Ministère de l'Enseignement Supérieur et de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Ligue Nationale contre le Cancer, and CNRS/Fondation ARC pour la Recherche sur le Cancer
Subjects: Saccharomyces cerevisiae Proteins, MESH: Mutation, Transcription, Genetic, MESH: Introns, MESH: RNA Precursors, MESH: Saccharomyces cerevisiae Proteins, Gene Expression Regulation, Fungal, RNA Precursors, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, MESH: RNA, Messenger, MESH: Sumoylation, MESH: Transcription, Genetic, Nuclear Proteins, Sumoylation, Introns, DNA-Binding Proteins, Nuclear Pore Complex Proteins, Cysteine Endopeptidases, MESH: Ribonucleoproteins, Ribonucleoproteins, Mutation, Nuclear Pore, RNA, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins, MESH: Gene Expression Regulation, Fungal, MESH: Nuclear Pore, MESH: Cysteine Endopeptidases, MESH: Nuclear Pore Complex Proteins
Abstract: International audience; Several nuclear pore-associated factors, including the SUMO-protease Ulp1, have been proposed to prevent the export of intron-containing messenger ribonucleoparticles (mRNPs) in yeast. However, the molecular mechanisms of this nuclear pore-dependent mRNA quality control, including the sumoylated targets of Ulp1, have remained unidentified. Here, we demonstrate that the apparent 'pre-mRNA leakage' phenotype arising upon ULP1 inactivation is shared by sumoylation mutants of the THO complex, an early mRNP biogenesis factor. Importantly, we establish that alteration of THO complex activity differentially impairs the expression of intronless and intron-containing reporter genes, rather than triggering bona fide 'pre-mRNA leakage'. Indeed, we show that the presence of introns within THO target genes attenuates the effect of THO inactivation on their transcription. Epistasis analyses further clarify that different nuclear pore components influence intron-containing gene expression at distinct stages. Ulp1, whose maintenance at nuclear pores depends on the Nup84 complex, impacts on THO-dependent gene expression, whereas the nuclear basket-associated Mlp1/Pml39 proteins prevent pre-mRNA export at a later stage, contributing to mRNA quality control. Our study thus highlights the multiplicity of mechanisms by which nuclear pores contribute to gene expression, and further provides the first evidence that intronic sequences can alleviate early mRNP biogenesis defects.
Published: 2015
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17. Potential for alternative intron–exon pairings in group II intron RmInt1 from Sinorhizobium meliloti and its relatives

Author: Nicolás Toro, François Michel, Maria do Carmo Costa, Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Grupo de Ecologıa Genética, Estacion, Granada, and Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)
Subjects: Models, Molecular, MESH: Introns, Sequence analysis, Molecular Sequence Data, MESH: Base Sequence, 03 medical and health sciences, Exon, MESH: RNA, Catalytic, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Catalytic, Letter to the Editor, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, Sinorhizobium meliloti, MESH: Molecular Sequence Data, Binding Sites, Splice site mutation, Base Sequence, biology, 030306 microbiology, MESH: Alternative Splicing, Alternative splicing, Ribozyme, Intron, Exons, Group II intron, biology.organism_classification, Molecular biology, Introns, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Alternative Splicing, RNA, Bacterial, MESH: Nucleic Acid Conformation, MESH: Binding Sites, biology.protein, Nucleic Acid Conformation, MESH: Exons, MESH: RNA, Bacterial, MESH: Sinorhizobium meliloti, MESH: Models, Molecular
Abstract: Ribozyme constructs derived from group II intron RmInt1 of Sinorhizobium meliloti self-splice in vitro when incubated under permissive conditions, but exon ligation is unusually inefficient when the 5′ exon is truncated close to the IBS2 intron-binding site. One plausible explanation for this observation is the presence of an alternative intron–exon pairing between an intron segment that overlaps with the EBS2 exon-binding site and a 5′ exon site located just distal of IBS2 relative to the splice junction. Strikingly, the existence of this pairing is supported by comparative sequence analysis of introns related to RmInt1.
Published: 2006
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18. Biogenesis and Intranuclear Trafficking of Human Box C/D and H/ACA RNPs

Author: Jády Be, Fayet E, Patricia Richard, Tamás Kiss, Weber M, Laboratoire de biologie moléculaire eucaryote (LBME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: RNA, Small Nucleolar, Transcription, Genetic, MESH: Introns, RNA Splicing, Active Transport, Cell Nucleus, Coiled Bodies, MESH: Active Transport, Cell Nucleus, Models, Biological, Biochemistry, Dyskerin, 03 medical and health sciences, Ribonucleoproteins, Small Nucleolar, MESH: Ribonucleoproteins, Small Nucleolar, MESH: RNA, MESH: RNA, Guide, Genetics, Humans, RNA, Small Nucleolar, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Guide RNA, Small nucleolar RNA, Telomerase, Molecular Biology, 030304 developmental biology, Ribonucleoprotein, Fibrillarin, 0303 health sciences, MESH: Humans, Chemistry, MESH: Transcription, Genetic, 030302 biochemistry & molecular biology, MESH: Models, Biological, MESH: Telomerase, RNA, MESH: Coiled Bodies, Introns, MESH: RNA Polymerase II, Cell biology, MESH: Ribonucleoproteins, MESH: Nucleic Acid Conformation, Ribonucleoproteins, Cajal body, RNA splicing, Nucleic Acid Conformation, RNA Polymerase II, MESH: RNA Splicing, RNA, Guide, Kinetoplastida
Abstract: Box C/D and H/ACA snoRNAs represent two abundant groups of small noncoding RNAs. The majority of box C/D and H/ACA snoRNAs function as guide RNAs in the site-specific 2'-O-methylation and pseudouridylation of rRNAs, respectively. The box C/D snoRNAs associate with fibrillarin, Nop56, Nop58, and 15.5K/NHPX proteins to form functional snoRNP particles, whereas all box H/ACA snoRNAs form complexes with the dyskerin, Nop10, Nhp2, and Gar1 snoRNP proteins. Recent studies demonstrate that the biogenesis of mammalian snoRNPs is a complex process that requires numerous trans-acting factors. Most vertebrate snoRNAs are posttranscriptionally processed from pre-mRNA introns, and the early steps of snoRNP assembly are physically and functionally coupled with the synthesis or splicing of the host pre-mRNA. The maturing snoRNPs follow a complicated intranuclear trafficking process that is directed by transport factors also involved in nucleocytoplasmic RNA transport. The human telomerase RNA (hTR) carries a box H/ACA RNA domain that shares a common Cajal-body-specific localization element with a subclass of box H/ACA RNAs, which direct pseudouridylation of spliceosomal snRNAs in the Cajal body. However, besides concentrating in Cajal bodies, hTR also accumulates at a small, structurally distinct subset of telomeres during S phase. This suggests that a cell-cycle-dependent, dynamic localization of hTR to telomeres may play an important regulatory role in human telomere synthesis.
Published: 2006
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19. Genetic background of HSH in three Polish families and a patient with an X;9 translocation

Author: Tiina Alitalo, André Hanauer, Ewa Pronicka, Roxanne Y Walder, R. Jalkanen, Henna Tyynismaa, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Introns, Vascular Endothelial Growth Factor D, Chromosomal translocation, MESH: Amino Acid Sequence, MESH: Base Sequence, Gene mutation, Translocation, Genetic, Genetics (clinical), X chromosome, Genetics, 0303 health sciences, MESH: Infant, Newborn, 030305 genetics & heredity, MESH: Infant, MESH: Translocation, Genetic, Pedigree, 3. Good health, MESH: Poland, Female, Chromosomes, Human, Pair 9, MESH: Magnesium Deficiency, MESH: Hypocalcemia, MESH: Mutation, MESH: Pedigree, Hypomagnesemia with secondary hypocalcemia, Molecular Sequence Data, TRPM Cation Channels, Translocation Breakpoint, Chromosome 9, Protein Serine-Threonine Kinases, Biology, MESH: Chromosomes, Human, X, 03 medical and health sciences, medicine, Humans, Amino Acid Sequence, 030304 developmental biology, Chromosomes, Human, X, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, Hypocalcemia, Genetic heterogeneity, MESH: TRPM Cation Channels, Breakpoint, Infant, Newborn, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Introns, MESH: Male, Mutation, MESH: Vascular Endothelial Growth Factor D, Poland, MESH: Chromosomes, Human, Pair 9, Magnesium Deficiency, MESH: Female
Abstract: International audience; Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients belonging to three families, and a HSH patient carrying an apparently balanced X;9 translocation. The translocation patient has long been considered as an example of the X-linked form of HSH. We identified six TRPM6 gene mutations, of which five were novel, in the Polish patients. All the alterations were either nonsense/splicing or missense mutations. The clinical picture of the patients was similar to the HSH patients reported earlier. No genotype-phenotype correlation could be detected. Sequencing did not reveal any TRPM6 or TRPM7 gene mutations in the female HSH patient with an X;9 translocation. Isolation of the translocation breakpoint showed that the chromosome 9 specific breakpoint mapped within satellite III repeat sequence. The X-chromosomal breakpoint was localised to the first intron of the vascular endothelial growth factor gene, VEGFD. No other sequence alterations were observed within the VEGFD gene. Even though the VEGFD gene was interrupted by the X;9 translocation, it seems unlikely that VEGFD is causing the translocation patient's HSH-like phenotype. Furthermore, re-evaluation of patient's clinical symptoms suggests that she did not have a typical HSH.
Published: 2005
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20. DNA Polymerase η Is Involved in Hypermutation Occurring during Immunoglobulin Class Switch Recombination

Author: Sandra Weller, Anne Stary, Claude-Agnès Reynaud, Alain Sarasin, Jean-Claude Weill, Said Aoufouchi, Ahmad Faili, Françoise Vuillier, Ribierre, Hélène, Développement du Systeme 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), Immuno-Hématologie et Immunopathologie, Institut Pasteur [Paris] (IP), Etude des relations instabilité génétique et cancer (ERIGC), Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], 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: MESH: Introns, DNA polymerase, DNA Mutational Analysis, DNA-Directed DNA Polymerase, MESH: Base Sequence, Gene mutation, Cytosine Deaminase, translesional DNA polymerases, 0302 clinical medicine, MESH: DNA-Directed DNA Polymerase, Immunology and Allergy, somatic mutation, MESH: DNA Mutational Analysis, Polymerase, Recombination, Genetic, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, B-Lymphocytes, 0303 health sciences, MESH: Middle Aged, biology, MESH: DNA, Cytidine deaminase, Middle Aged, MESH: Immunoglobulin Class Switching, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Immunologic Memory, Female, MESH: Recombination, Genetic, Adult, MESH: DNA Primers, MESH: Somatic Hypermutation, Immunoglobulin, Molecular Sequence Data, Immunology, xeroderma pigmentosum variant syndrome, Somatic hypermutation, Article, Immunoglobulin Class Switch Recombination, 03 medical and health sciences, Tandem repeat, Cytidine Deaminase, MESH: B-Lymphocytes, Humans, DNA Primers, MESH: Xeroderma Pigmentosum, MESH: Cytidine Deaminase, 030304 developmental biology, Xeroderma Pigmentosum, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Cytosine Deaminase, MESH: Adult, DNA, Immunoglobulin Class Switching, Molecular biology, Introns, Immunoglobulin class switching, pol η, biology.protein, Somatic Hypermutation, Immunoglobulin, Immunologic Memory, MESH: Female, 030215 immunology
Abstract: Base substitutions, deletions, and duplications are observed at the immunoglobulin locus in DNA sequences involved in class switch recombination (CSR). These mutations are dependent upon activation-induced cytidine deaminase (AID) and present all the characteristics of the ones observed during V gene somatic hypermutation, implying that they could be generated by the same mutational complex. It has been proposed, based on the V gene mutation pattern of patients with the cancer-prone xeroderma pigmentosum variant (XP-V) syndrome who are deficient in DNA polymerase η (pol η), that this enzyme could be responsible for a large part of the mutations occurring on A/T bases. Here we show, by analyzing switched memory B cells from two XP-V patients, that pol η is also an A/T mutator during CSR, in both the switch region of tandem repeats as well as upstream of it, thus suggesting that the same error-prone translesional polymerases are involved, together with AID, in both processes.
Published: 2004
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21. Molecular characterization of major histocompatibility complex class 1 (MHC-I) from squirrel monkeys ( Saimiri sciureus )

Author: Mirdad Kazanji, Rolf Fendel, Jean-Michel Heraud, Anne Lavergne, Hervé Pascalis, Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), and Centre International de Recherches Médicales de Franceville (CIRMF)
Subjects: MESH: Introns, MESH: Sequence Homology, Amino Acid, Genes, MHC Class I, MESH: Amino Acid Sequence, MESH: Base Sequence, MESH: Histocompatibility Antigens Class I, 0302 clinical medicine, HLA Antigens, MESH: HLA-A2 Antigen, Coding region, MESH: Animals, Cloning, Molecular, MESH: Phylogeny, Saimiri, MESH: HLA Antigens, Phylogeny, Genetics, 0303 health sciences, biology, Squirrel monkey, Exons, MESH: Genes, MHC Class I, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Signal peptide, DNA, Complementary, Molecular Sequence Data, Immunology, Human leukocyte antigen, Major histocompatibility complex, MESH: Sequence Homology, Nucleic Acid, MESH: Saimiri, 03 medical and health sciences, Sequence Homology, Nucleic Acid, HLA-A2 Antigen, MHC class I, Animals, MESH: Cloning, Molecular, Amino Acid Sequence, Alleles, 030304 developmental biology, HLA-G Antigens, MESH: Molecular Sequence Data, Base Sequence, Sequence Homology, Amino Acid, MESH: Alleles, Histocompatibility Antigens Class I, Saimiri sciureus, MESH: DNA, Complementary, biology.organism_classification, Introns, biology.protein, MESH: Exons, CD8, 030215 immunology
Abstract: International audience; Little is known about the major histocompatibility complex (MHC) class 1 in squirrel monkeys ( Saimiri sciureus). We cloned, sequenced and characterized two alleles and the cDNA of the coding region of MHC class 1 in these New World monkeys. Phylogenetic analyses showed that these sequences are related to HLA class 1 genes ( HLA-A and HLA-G). The structure and organization of one of the two identified clones was similar to that of a class 1 MHC gene ( HLA-A2). All the exon/intron splice acceptor/donor sites are conserved and their locations correspond to the HLA-A2 gene. The sequences of the newly described cDNAs reveal that they code for the characteristic class 1 MHC proteins, with all the features thought necessary for cell surface expression. Typical sequences for the leader peptide, alpha(1), alpha(2), alpha(3), transmembrane and cytoplasmic domains were found.
Published: 2003
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22. Extreme genome diversity in the hyper-prevalent parasitic eukaryote Blastocystis

Author: Dayana E. Salas-Leiva, C. Graham Clark, Martin Kolisko, Frédérique Hilliou, Mark van der Giezen, Courtney W. Stairs, Hiroshi Suga, Bernard Henrissat, Andrew J. Roger, Vladimír Klimeš, Anastasios D. Tsaousis, John M. Archibald, Steven G. Ball, Eleni Gentekaki, Richard A. Rachubinski, Darren M. Soanes, Emily K. Herman, Mary J. Klute, Marek Eliáš, Alexander Schlacht, Joel B. Dacks, Shehre-Banoo Malik, Bruce A. Curtis, Arthur W. Pightling, Maria Cecilia Arias, Laura Eme, Faculty of Computer Science, Dalhousie University [Halifax], Architecture et fonction des macromolécules biologiques (AFMB), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Institut Sophia Agrobiotech (ISA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology [Alberta], Univerity of Alberta, Biotechnology and Biological Sciences Research Council [BB/M009971/1], Czech Science Foundation [13-33039S, 15-16406S], Wellcome Trust [078566/A/05/Z], Wellcome Trust, Japan Society for the Promotion of Science [JSPS KAKENHI 16K07468], Canadian Institutes of Health Research [FDN-143289], NSERC [RES0021028], Canadian Institutes for Health Research [MOP 142349], Gentekaki, Eleni, Roger, Andrew J., Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Sophia Agrobiotech [Sophia Antipolis] (ISA), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), CNRS, Université de Lille, Faculty of Sciences (Ostrava, Czech Republic), University of Alberta, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], Architecture et fonction des macromolécules biologiques [AFMB], Institut Sophia Agrobiotech [ISA], Hiroshima University, University of Exeter, Canadian Institute for Advanced Research [CIFAR], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], London School of Hygiene and Tropical Medicine [LSHTM], Institut National de la Recherche Agronomique (INRA)-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)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Introns, MESH: Carbohydrate Metabolism, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Codon, Terminator, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Genome, Database and Informatics Methods, Sequence alignment, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), Energy-Producing Organelles, Protozoans, Genetics, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, General Neuroscience, Methods and Resources, Biochemistry and Molecular Biology, Eukaryota, Genomics, Proteases, MESH: Genome, Protozoan, Vitamin biosynthesis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Enzymes, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Mitochondria, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Proteome, Codon, Terminator, Carbohydrate Metabolism, Cellular Structures and Organelles, General Agricultural and Biological Sciences, Sequence Analysis, MESH: Blastocystis, QH301-705.5, Bioinformatics, 030106 microbiology, Bioenergetics, Genome Complexity, Research and Analysis Methods, MESH: Gastrointestinal Microbiome, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Species Specificity, Humans, MESH: Species Specificity, Gene family, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Gene, Comparative genomics, blastocystis, introns, comparative genomics, eukaryota, mitochondria, genomic databases, sequence alignment, Blastocystis, MESH: Humans, General Immunology and Microbiology, Organisms, Biology and Life Sciences, Computational Biology, Proteins, Cell Biology, Genome Analysis, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitic Protozoans, Introns, Gastrointestinal Microbiome, Biological Databases, 030104 developmental biology, Enzymology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Genome, Protozoan, Genomic databases, Biokemi och molekylärbiologi
Abstract: Blastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%–61% median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane-trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize α-glucans rather than β-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease., Author summary Blastocystis are unicellular eukaryotic organisms related to algae and some plant pathogens. They are common constituents of the human gut microbial community, colonizing approximately 1 billion humans worldwide. Whether their presence is harmful or not continues to be hotly debated. Part of the uncertainty stems from the fact that at least 17 subtypes have been identified from various mammalian hosts, including 9 from humans. To better characterize and understand Blastocystis, we have sequenced and annotated the genome for subtype 1 and compared it with previous genomic results for subtypes 7 and 4. The comparisons revealed considerable differences between the 3 sequenced subtypes for a number of genomic features like DNA base composition, size of genome, number of genes, and number of introns. We also examined various biochemical pathways and cellular systems in the context of the full gene complement to better understand the biology of Blastocystis, including some of its more unusual features like a mitochondrion related organelle. We also identified subtype-specific gene family expansions that may be related to virulence. Finally, we showed that Blastocystis appears to have most of the genes necessary for sexual reproduction. This study provides resources and hypotheses for future investigations into the biology and potential pathogenicity of these common gut microbes.
Published: 2017
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23. Brr2p carboxy-terminal Sec63 domain modulates Prp16 splicing RNA helicase

Author: Cordin, Olivier, Hahn, Daniela, Alexander, Ross, Gautam, Amit, Saveanu, Cosmin, Barrass, J David, Beggs, Jean D, Expression Génétique Microbienne (EGM (UMR_8261 / FRE_3630)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust Centre for Cell Biology, University of Edinburgh, Génétique des Interactions macromoléculaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust [087551 to J.D.Beggs, 092076 core fund-ing grant], Darwin Trust of Edinburgh [studentships toD.H. and A.G.], French ‘Agence Nationale de la Recherche’[ANR-08-JCJC-0019-01 to C.S.], Royal Society [DarwinTrust Research Professorship to J.D.Beggs]. Funding foropen access charge: Wellcome Trust., ANR-08-JCJC-0019,GENO-GIM,Obtention d'une carte d'interactions génétiques à l'échelle génomique chez la levure(2008), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Génétique des Interactions macromoléculaires / Genetics of Macromolecular Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut de biologie physico-chimique (IBPC)
Subjects: Hot Temperature, Saccharomyces cerevisiae Proteins, MESH: Mutation, MESH: Introns, RNA Splicing, MESH: Hot Temperature, DEAD-box RNA Helicases, MESH: Protein Structure, Tertiary, MESH: Saccharomyces cerevisiae Proteins, MESH: RNA, Genetics, MESH: Adenosine Triphosphatases, MESH: DEAD-box RNA Helicases, Alleles, Adenosine Triphosphatases, Nucleic Acid Enzymes, MESH: Ribonucleoproteins, Small Nuclear, MESH: RNA Helicases, MESH: Alleles, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Ribonucleoproteins, Small Nuclear, Introns, Protein Structure, Tertiary, MESH: RNA Splicing Factors, Mutation, RNA, RNA Splicing Factors, MESH: RNA Splicing, RNA Helicases
Abstract: International audience; RNA helicases are essential for virtually all cellular processes, however, their regulation is poorly understood. The activities of eight RNA helicases are required for pre-mRNA splicing. Amongst these, Brr2p is unusual in having two helicase modules, of which only the amino-terminal helicase domain appears to be catalytically active. Using genetic and biochemical approaches, we investigated interaction of the carboxy-terminal helicase module, in particular the carboxy-terminal Sec63-2 domain, with the splicing RNA helicase Prp16p. Combining mutations in BRR2 and PRP16 suppresses or enhances physical interaction and growth defects in an allele-specific manner, signifying functional interactions. Notably, we show that Brr2p Sec63-2 domain can modulate the ATPase activity of Prp16p in vitro by interfering with its ability to bind RNA. We therefore propose that the carboxy-terminal helicase module of Brr2p acquired a regulatory function that allows Brr2p to modulate the ATPase activity of Prp16p in the spliceosome by controlling access to its RNA substrate/cofactor.
Published: 2014
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24. Les mutations du gène TMEM240 provoquent l'ataxie spinocérébelleuse 21 avec un retard mental et des troubles cognitifs sévères

Author: Delplanque, Jérôme, Devos, David, Huin, Vincent, Genet, Alexandre, Sand, Olivier, Moreau, Caroline, Goizet, Cyril, Charles, Perrine, Anheim, Mathieu, Monin, Marie Lorraine, Buée, Luc, Destée, Alain, Grolez, Guillaume, Delmaire, Christine, Dujardin, Kathy, Dellacherie, Delphine, Brice, Alexis, Stevanin, Giovanni, Strubi-Vuillaume, Isabelle, Durr, Alexandra, Sablonnière, Bernard, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Biologie Pathologie [CHRU Lille] (Pôle de Pathologie), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departement de Neuroradiologie [Lille], Service de neuropédiatrie [CHU Lille], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), HESAM Université (HESAM), HUIN, Vincent, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: MESH: Mutation / physiology, MESH: Intellectual Disability / genetics, MESH: Introns, MESH: Pedigree, MESH: Age of Onset, MESH: Exome / genetics, MESH: Genetic Linkage, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, MESH: Membrane Proteins / genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Spinocerebellar Degenerations / pathology, MESH: Intellectual Disability / psychology, MESH: Chromosomes, Human, Pair 1 / genetics, MESH: Child, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: DNA Mutational Analysis, MESH: Spinocerebellar Degenerations / psychology, MESH: Cohort Studies, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Conserved Sequence, MESH: Humans, MESH: Molecular Sequence Data, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, MESH: Child, Preschool, MESH: Membrane Proteins / physiology, MESH: Cognition Disorders / psychology, MESH: Neuropsychological Tests, MESH: Polymerase Chain Reaction, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Infant, MESH: Male, MESH: France, MESH: Cognition Disorders / genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Young Adult, TMEM240, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Spinocerebellar ataxia, MESH: Intelligence Tests, MESH: Female, exome, MESH: Spinocerebellar Degenerations / genetics
Abstract: International audience; Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C4T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C4T/p.P170L, c.239C4T/p.T80M, c.346C4T/p.R116C, c.445G4A/p.E149K, c.511C4T/p.R171W), and a stop mutation (c.489C4G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.
Published: 2014
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25. Les mutations du gène TMEM240 provoquent l'ataxie spinocérébelleuse 21 avec un retard mental et des troubles cognitifs sévères

Author: Giovanni Stevanin, Luc Buée, Olivier Sand, David Devos, Guillaume Grolez, Marie Lorraine Monin, Alexandra Durr, Caroline Moreau, Kathy Dujardin, Bernard Sablonnière, Vincent Huin, Alexis Brice, Cyril Goizet, Alexandre Genet, Alain Destée, Mathieu Anheim, Perrine Charles, Christine Delmaire, Jérôme Delplanque, Isabelle Strubi-Vuillaume, Delphine Dellacherie, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Biologie Pathologie [CHRU Lille] (Pôle de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Departement de Neuroradiologie [Lille], Service de neuropédiatrie [CHU Lille], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and HESAM Université (HESAM)
Subjects: Cerebellum, MESH: Intellectual Disability / genetics, MESH: Introns, MESH: Exome / genetics, MESH: Amino Acid Sequence, MESH: Membrane Proteins / genetics, MESH: Spinocerebellar Degenerations / pathology, Autosomal dominant cerebellar ataxia, MESH: Child, Missense mutation, MESH: DNA Mutational Analysis, Exome, MESH: Spinocerebellar Degenerations / psychology, MESH: Cohort Studies, Exome sequencing, Genetics, MESH: Conserved Sequence, MESH: Membrane Proteins / physiology, MESH: Neuropsychological Tests, MESH: Cognition Disorders / psychology, MESH: Infant, 3. Good health, medicine.anatomical_structure, MESH: Young Adult, Spinocerebellar ataxia, medicine.symptom, MESH: Spinocerebellar Degenerations / genetics, MESH: Mutation / physiology, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, MESH: Pedigree, MESH: Age of Onset, MESH: Genetic Linkage, Biology, MESH: Intellectual Disability / psychology, MESH: Chromosomes, Human, Pair 1 / genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Quantitative Biology - Genomics, Genomics (q-bio.GN), MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Cerebellar ataxia, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Child, Preschool, MESH: Polymerase Chain Reaction, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, MESH: France, MESH: Cognition Disorders / genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, FOS: Biological sciences, TMEM240, Neurology (clinical), MESH: Intelligence Tests, MESH: Female, exome
Abstract: Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240 , was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment. * Abbreviations : SCA : spinocerebellar ataxia SPATAX : network of hereditary forms of spastic paraplegias and cerebellar ataxias
Published: 2014
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26. Morphological variation in the freshwater blenny Salaria fluviatilis from Corsican rivers: adaptive divergence, phenotypic plasticity or both?

Author: Magnan, P., Proulx, R., Berrebi, P., Blondel, J., Perret, P., Roché, B., Université du Québec à Trois-Rivières (UQTR), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Université Paul-Valéry - Montpellier 3 (UPVM)-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)-Institut de Recherche pour le Développement (IRD [France-Sud]), and Service de l'eau et des milieux aquatiques
Subjects: Male, Polymorphism, Genetic, MESH: Introns, MESH: Water Movements, MESH: Genetics, Population, Adaptation, Physiological, MESH: Adaptation, Physiological, Introns, MESH: Male, Perciformes, MESH: Rivers, MESH: France, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Genetics, Population, Rivers, MESH: Perciformes, MESH: Polymorphism, Genetic, Water Movements, Animals, Female, MESH: Animals, MESH: Ecosystem, France, MESH: Female, Ecosystem
Abstract: International audience; The first goal of this study was to determine whether morphological variation in the freshwater blenny Salaria fluviatilis results in spatially structured populations distributed around Corsica, France, which would suggest genetically differentiated populations through reproductive isolation by distance. The second goal was to determine whether some morphological traits are related to water velocity, one of the most contrasting habitat characteristics in these rivers, which would suggest an adaptation to local conditions. The results showed that the morphology of S. fluviatilis differed among the three main geographic areas studied in Corsica and that geographically distant populations of S. fluviatilis were less similar morphologically and genetically than close ones. The results also indicated that the morphological differences among populations conformed to functional expectations. Overall, the results suggest that the morphological variation of S. fluviatilis from Corsican rivers is an adaptive response to water velocity and that these populations are in a process of reproductive isolation by distance.
Published: 2014
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27. Variation in FTO contributes to childhood obesity and severe adult obesity

Author: Stéphane Cauchi, Cécile Lecoeur, Peter Kovacs, Jacques Weill, Jérôme Delplanque, Pierre Bougnères, Claire Levy-Marchal, Vincent Vatin, Wieland Kiess, Serge Hercberg, Sophie Gallina, Emmanuelle Durand, Lena M. S. Carlsson, Jean-Claude Chèvre, Emmanuel Vaillant, Natascha Potoczna, Beverley Balkau, Antje Körner, Catherine Le Stunff, Juan Ruiz, François Pattou, Fritz F. Horber, David Meyre, Philippe Froguel, Michel Marre, Peter Jacobson, Christian Dina, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie de Lille (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Développement artériel, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mercator Océan, Société Civile CNRS Ifremer IRD Météo-France SHOM, Centre de Physique Théorique - UMR 6207 (CPT), Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Universidad Politécnica de Madrid (UPM), Laboratoire d'Ingénierie des Projets Industriels, Ecole Nationale Supérieure de Synthèses, de Procédés et d'Ingénierie Chimiques d'Aix-Marseille (LIPI - ENSSPICAM), Université Paul Cézanne - Aix-Marseille 3, Centro de Estudios en Semiconductores (C.E.S.), Dpto. Física, Fac. Ciencias, Universidad de los Andes [Bogota], Instituto de Quimica, Universidade Estadual de Campinas (UNICAMP), Laboratoire de chimie organique et organométallique (LCOO), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Liquides Ioniques et Interfaces Chargées (LI2C), Centre National de la Recherche Scientifique (CNRS)-ESPCI ParisTech-Université Pierre et Marie Curie - Paris 6 (UPMC), Dr. Horber Adipositas Stiftung, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie cardiovasculaire et métabolique, Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Universidad de los Andes [Bogota] (UNIANDES), Universidade Estadual de Campinas = University of Campinas (UNICAMP), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université de Bordeaux (UB), Centre National de la Recherche Scientifique (CNRS)-Université de Toulon (UTLN)-Université de Provence - Aix-Marseille 1-Université de la Méditerranée - Aix-Marseille 2, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie de Lille ( IBL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ), Physique, Université de Lille, Sciences Humaines et Sociales, Institut de Chimie de la Matière Condensée de Bordeaux ( ICMCB ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Physique Théorique - UMR 6207 ( CPT ), Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Université de Toulon ( UTLN ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad Politécnica de Madrid ( UPM ), Laboratoire d'Ingénierie des Projets Industriels, Ecole Nationale Supérieure de Synthèses, de Procédés et d'Ingénierie Chimiques d'Aix-Marseille ( LIPI - ENSSPICAM ), Universidad de Los Andes, Universidade Estadual de Campinas ( UNICAMP ), Laboratoire de chimie organique et organométallique ( LCOO ), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique ( CNRS ), Centre de Physique Théorique - UMR 7332 ( CPT ), Aix Marseille Université ( AMU ) -Université de Toulon ( UTLN ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Jeanne de Flandre [Lille], Liquides Ioniques et Interfaces Chargées ( LI2C ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires, 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 - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, MESH: Introns, Variation (Genetics), FTO gene, Body Mass Index, MESH: Variation (Genetics), Cohort Studies, 0302 clinical medicine, MESH : Child, SH2B1, MESH: Child, MESH: Obesity, MESH : Female, Age of Onset, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Child, MESH: Cohort Studies, Adiposity, 0303 health sciences, MESH: Middle Aged, MESH : Variation (Genetics), Genetics of obesity, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, INSIG2, MESH: Genetic Predisposition to Disease, MESH : Chromosomes, Human, Pair 16, Single Nucleotide, MESH : Adult, Middle Aged, MESH: Case-Control Studies, MESH : Age of Onset, Europe, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Composition, MESH : Obesity, Female, Human, Adult, MESH : Case-Control Studies, medicine.medical_specialty, MESH : Male, MESH : Body Composition, MESH: Age of Onset, MESH : Europe, MESH : Cohort Studies, 030209 endocrinology & metabolism, Biology, MESH : Introns, Chromosomes, Childhood obesity, MESH: Body Mass Index, 03 medical and health sciences, MESH : Adiposity, Internal medicine, Genetics, medicine, Humans, MESH : Middle Aged, Genetic Predisposition to Disease, Obesity, Polymorphism, MESH: Adiposity, 030304 developmental biology, MESH: Humans, Pair 16, MESH : Humans, MESH: Adult, MESH: Body Composition, medicine.disease, Introns, MESH: Male, MESH : Body Mass Index, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Attributable risk, MESH : Genetic Predisposition to Disease, MESH: Europe, MESH: Female, MESH: Chromosomes, Human, Pair 16
Abstract: The authors identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. They conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.
Published: 2007
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28. Extensive degradation of RNA precursors by the exosome in wild-type cells

Author: Bertrand Séraphin, Alice Lebreton, Lars M. Steinmetz, Rajani Kanth Gudipati, Alain Jacquier, Zhenyu Xu, Domenico Libri, Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Génétique des Interactions macromoléculaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Molecular Biology Laboratory [Heidelberg] (EMBL), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Danish National Research Foundation, Center for mRNP Biogenesis and Metabolism (D.L.), the ANR (D.L. and A.J., ANR-08-Blan-0038), the CNRS (D.L., A.J., and B.S.), Institut Pasteur (A.J.), La Ligue Nationale Contre le Cancer Equipe Labellisée 2011 (B.S.), the ESF EUROCORES RNA quality (D.L. and B.S.) and IGBMC (B.S.), and the National Institutes of Health (L.M.S.). R.K.G. received a PhD fellowship from Région Ile de France and a 'Roux' postdoctoral fellowship from Pasteur Institute. This research was carried out within the scope of the Associated European Laboratory LEA 'Laboratory of Nuclear RNA Metabolism.', ANR-08-BLAN-0038,CutReg,From transcriptional noise to the sound of regulation(2008), Génétique des Interactions macromoléculaires / Genetics of Macromolecular Interactions, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Polyadenylation, Exosome complex, MESH: Introns, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Substrate Specificity, 0302 clinical medicine, MESH: Saccharomyces cerevisiae Proteins, RNA, Transfer, RNA Precursors, RNA Processing, Post-Transcriptional, Small nucleolar RNA, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Exosome Multienzyme Ribonuclease Complex, Non-coding RNA, MESH: Saccharomyces cerevisiae, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, MESH: Exosome Multienzyme Ribonuclease Complex, RNA splicing, MESH: RNA Processing, Post-Transcriptional, MESH: RNA, Small Nucleolar, Saccharomyces cerevisiae Proteins, MESH: Mutation, MESH: RNA Precursors, Saccharomyces cerevisiae, Biology, Article, 03 medical and health sciences, MESH: Gene Expression Profiling, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA, Small Nucleolar, MESH: Blotting, Northern, Molecular Biology, 030304 developmental biology, MESH: RNA, Fungal, Gene Expression Profiling, RNA, RNA, Fungal, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Blotting, Northern, MESH: RNA, Transfer, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Introns, RNA, Ribosomal, Mutation, TRAMP complex, MESH: Oligonucleotide Array Sequence Analysis, MESH: RNA, Ribosomal, MESH: Substrate Specificity, 030217 neurology & neurosurgery
Abstract: International audience; The exosome is a complex involved in the maturation of rRNA and sn-snoRNA, in the degradation of short-lived noncoding RNAs, and in the quality control of RNAs produced in mutants. It contains two catalytic subunits, Rrp6p and Dis3p, whose specific functions are not fully understood. We analyzed the transcriptome of combinations of Rrp6p and Dis3p catalytic mutants by high-resolution tiling arrays. We show that Dis3p and Rrp6p have both overlapping and specific roles in degrading distinct classes of substrates. We found that transcripts derived from more than half of intron-containing genes are degraded before splicing. Surprisingly, we also show that the exosome degrades large amounts of tRNA precursors despite the absence of processing defects. These results underscore the notion that large amounts of RNAs produced in wild-type cells are discarded before entering functional pathways and suggest that kinetic competition with degradation proofreads the efficiency and accuracy of processing.
Published: 2012
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29. BRCA2 deep intronic mutation causing activation of a cryptic exon: opening toward a new preventive therapeutic strategy

Author: Mélanie Léoné, Christine Coutanson, Sylvie Mazoyer, Olga M. Sinilnikova, Monique Buisson, Christine Lasset, Olga Anczuków, Alain Calender, Groupe de recherche sur la socialisation (GRS), Université Lumière - Lyon 2 (UL2)-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], 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, Equipe 4, 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)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Introns, MESH: Pedigree, government.form_of_government, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, 030304 developmental biology, Genetics, Antisense therapy, 0303 health sciences, Splice site mutation, MESH: Humans, MESH: Alternative Splicing, Alternative splicing, Intron, 3. Good health, MESH: Ovarian Neoplasms, Oncology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), RNA splicing, government, MESH: Exons, MESH: Female, MESH: Genes, BRCA1, MESH: Breast Neoplasms, MESH: Genes, BRCA2, Minigene
Abstract: Purpose: Diagnostic screening of the BRCA1/2 genes in breast cancer families is mostly done on genomic DNA. For families with a very strong family history and no mutation identified in the coding sequences or the exon–intron boundaries, BRCA1/2 transcripts' analysis is an efficient approach to uncover gene inversion and pre-mRNA splicing defaults missed by conventional DNA-based protocols. Experimental Design: We analyzed RNA from patients of negative BRCA families by reverse transcriptase PCR and identified an insertion in one family that we characterized by sequencing and by using a minigene splicing assay. More than 2,000 additional BRCA1/2 negative families were subsequently screened for this mutation using a dedicated PCR approach. Results: Nine families were found to harbor a BRCA2 mutant transcript containing a 95-nucleotide cryptic exon between exons 12 and 13. This cryptic exon results from a new mutation located deep into intron 12, c.6937+594T > G, which reinforces the strength of a preexisting 5′ splice site, turning it into a perfect consensus sequence. It is systematically included in transcripts produced by the mutant allele in cells from mutation carriers or produced by a mutant splicing reporter minigene. The inclusion of the cryptic exon was prevented when we cotransfected the minigene with antisense oligonucleotides complementary to the 3′ or mutated 5′ splice sites. Conclusion: This first deep intronic BRCA mutation emphasizes the importance of analyzing RNA to provide comprehensive BRCA1/2 diagnostic tests and opens the possibility of using antisense therapy in the future as an alternative strategy for cancer prevention. Clin Cancer Res; 18(18); 4903–9. ©2012 AACR.
Published: 2012
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30. Globally diverse Toxoplasma gondii isolates comprise six major clades originating from a small number of distinct ancestral lineages

Author: Asis Khan, D. Majumdar, Xing-Quan Zhu, Peng Zhou, Marie-Laure Dardé, Daniel Ajzenberg, James W. Ajioka, L. David Sibley, Benjamin M. Rosenthal, Chunlei Su, Jitender P. Dubey, Centre National de Référence (CNR) Toxoplasmose/Toxoplasma Biological Resource Center (BRC) (CNR Toxoplasmose-Toxoplasma BRC), CHU Limoges, Université de Limoges (UNILIM), Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Molecular Microbiology, and University of Washington [Seattle]
Subjects: Genetic Markers, MESH: Geography, MESH: Introns, Molecular Sequence Data, Population Dynamics, 030231 tropical medicine, MESH: Genetics, Population, Biology, MESH: Base Sequence, MESH: Genetic Markers, Genome, MESH: Genetic Loci, Haplogroup, Gene flow, 03 medical and health sciences, 0302 clinical medicine, MESH: Genetic Variation, Clade, MESH: Phylogeny, Gene, Phylogeny, 030304 developmental biology, Comparative genomics, Genetics, 0303 health sciences, Genetic diversity, Multidisciplinary, MESH: Molecular Sequence Data, Base Sequence, Geography, MESH: Polymorphism, Restriction Fragment Length, MESH: Toxoplasma, Genetic Variation, MESH: Haplotypes, Biological Sciences, MESH: Population Dynamics, Introns, Genetics, Population, Haplotypes, Genetic Loci, Genetic marker, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Microsatellite Repeats, Toxoplasma, Polymorphism, Restriction Fragment Length, Microsatellite Repeats
Abstract: Marked phenotypic variation characterizes isolates of Toxoplasma gondii, a ubiquitous zoonotic parasite that serves as an important experimental model for studying apicomplexan parasites. Progress in identifying the heritable basis for clinically and epidemiologically significant differences requires a robust system for describing and interpreting evolutionary subdivisions in this prevalent pathogen. To develop such a system, we have examined more than 950 isolates collected from around the world and genotyped them using three independent sets of polymorphic DNA markers, sampling 30 loci distributed across all nuclear chromosomes as well as the plastid genome. Our studies reveal a biphasic pattern consisting of regions in the Northern Hemisphere where a few, highly clonal and abundant lineages predominate; elsewhere, and especially in portions of South America are characterized by a diverse assemblage of less common genotypes that show greater evidence of recombination. Clustering methods were used to organize the marked genetic diversity of 138 unique genotypes into 15 haplogroups that collectively define six major clades. Analysis of gene flow indicates that a small number of ancestral lineages gave rise to the existing diversity through a process of limited admixture. Identification of reference strains for these major groups should facilitate future studies on comparative genomics and identification of genes that control important biological phenotypes including pathogenesis and transmission.
Published: 2012
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31. A Critical Role of Perinuclear Filamentous Actin in Spatial Repositioning and Mutually Exclusive Expression of Virulence Genes in Malaria Parasites

Author: Jose-Juan Lopez-Rubio, Yilong Zhang, Aurélie Claes, Magalie Duchateau, Qingfeng Zhang, Abdelkader Namane, Weiqing Pan, Xiaonan Fang, Artur Scherf, Yufu Huang, Tongji University School of Medicine [Shanghai, China], Biologie des Interactions Hôte-Parasite, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The Secondary Military Medical University [Shanghai, China], Plateforme de Protéomique / Proteomics platform, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Protéomique (Plate-Forme), Institut Pasteur [Paris], This work was supported by the National Basic Research Program (973 Program) in China (2007CB513100), the National Natural Science Foundation of China (No. 30430610), an ERC Advanced Grant (PlasmoEscape 250320), and European Commission FP7 programs EVIMalaR and ANR Blanc International PARACTIN., ANR-10-INTB-1301,PARACTIN,Impact of actin and actin-related proteins in parasitic human infections(2010), European Project: 250320,EC:FP7:ERC,ERC-2009-AdG,PLASMOESCAPE(2010), European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)
Subjects: MESH: Cell Nucleus, Cancer Research, MESH: Protein Transport, MESH: Introns, Biology, MESH: Actins, Microbiology, Filamentous actin, Article, 03 medical and health sciences, MESH: Plasmids, Virology, Immunology and Microbiology(all), Gene expression, Antigenic variation, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Molecular Biology, MESH: Protozoan Proteins, Actin, MESH: Plasmodium falciparum, 030304 developmental biology, MESH: Virulence Factors, Genetics, Regulation of gene expression, 0303 health sciences, MESH: Humans, MESH: Malaria, Falciparum, 030302 biochemistry & molecular biology, Intron, Phenotype, MESH: Gene Expression Regulation, 3. Good health, Parasitology
Abstract: International audience; Many microbial pathogens, including the malaria parasite Plasmodium falciparum, vary surface protein expression to evade host immune responses. P. falciparium antigenic variation is linked to var gene family-encoded clonally variant surface protein expression. Mututally exclusive var gene expression is partially controlled by spatial positioning; silent genes are retained at distinct perinuclear sites and relocated to transcriptionally active locations for monoallelic expression. We show that var introns can control this process and that var intron addition relocalizes episomes from a random to a perinuclear position. This var intron-regulated nuclear tethering and repositioning is linked to an 18 bp nuclear protein-binding element that recruits an actin protein complex. Pharmacologically induced F-actin formation, which is restricted to the nuclear periphery, repositions intron-carrying episomes and var genes and disrupts mutually exclusive var gene expression. Thus, actin polymerization relocates var genes from a repressive to an active perinuclear compartment, which is crucial for P. falciparium phenotypic variation and pathogenesis.
Published: 2011
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32. Preventing dangerous nonsense: selection for robustness to transcriptional error in human genes

Author: Cusack, Brian, Arndt, Peter, Duret, L., Roest Crollius, Hugues, Department Computational Molecular Biology [MPIMG Berlin], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), 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), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Autard, Delphine, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris
Subjects: MESH: Histones, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Amino Acids, MESH: Humans, MESH: Gene Expression, MESH: Codon, MESH: Introns, MESH: Drosophila, MESH: Transcription, Genetic, MESH: RNA Stability, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Genes, MESH: Nonsense Mediated mRNA Decay, MESH: Animals, MESH: Genome, MESH: Codon, Nonsense, MESH: Exons, MESH: Mice, MESH: Genome, Human, MESH: Evolution, Molecular
Abstract: International audience; Nonsense Mediated Decay (NMD) degrades transcripts that contain a premature STOP codon resulting from mistranscription or missplicing. However NMD's surveillance of gene expression varies in efficiency both among and within human genes. Previous work has shown that the intron content of human genes is influenced by missplicing events invisible to NMD. Given the high rate of transcriptional errors in eukaryotes, we hypothesized that natural selection has promoted a dual strategy of "prevention and cure" to alleviate the problem of nonsense transcriptional errors. A prediction of this hypothesis is that NMD's inefficiency should leave a signature of "transcriptional robustness" in human gene sequences that reduces the frequency of nonsense transcriptional errors. For human genes we determined the usage of "fragile" codons, prone to mistranscription into STOP codons, relative to the usage of "robust" codons that do not generate nonsense errors. We observe that single-exon genes have evolved to become robust to mistranscription, because they show a significant tendency to avoid fragile codons relative to robust codons when compared to multi-exon genes. A similar depletion is evident in last exons of multi-exon genes. Histone genes are particularly depleted of fragile codons and thus highly robust to transcriptional errors. Finally, the protein products of single-exon genes show a strong tendency to avoid those amino acids that can only be encoded using fragile codons. Each of these observations can be attributed to NMD deficiency. Thus, in the human genome, wherever the "cure" for nonsense (i.e. NMD) is inefficient, there is increased reliance on the strategy of nonsense "prevention" (i.e. transcriptional robustness). This study shows that human genes are exposed to the deleterious influence of transcriptional errors. Moreover, it suggests that gene expression errors are an underestimated phenomenon, in molecular evolution in general and in selection for genomic robustness in particular.
Published: 2011
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33. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA

Author: Charles Marcaillou, Pierre-Simon Jouk, Françoise Clerget-Darpoux, Joelle Chastang, Sheela Nampoothiri, Emmanuel Tubacher, Renaud Touraine, Audrey Labalme, Francis Rousseau, Patrick Edery, Annick Toutain, Mourad Sahbatou, Carol Wise, Faiza Senni, Anne-Louise Leutenegger, Elisabeth Steichen, Siren Berland, Damien Sanlaville, Michael B. Bober, 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 cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de Cytogenetique Constitutionnelle, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Amrita Institute of Medical Sciences and Research Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), DYCTIM, 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)-Registre des Handicaps de l'Enfant et Observatoire Périnatal Isère, RHEOP-RHEOP, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, INTEGRAGEN, IntegraGen, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Spliceosome, MESH: Pedigree, MESH: Introns, [SDV]Life Sciences [q-bio], MESH: Base Pairing, MESH: Fetal Growth Retardation, MESH: Chromosomes, Human, Pair 2, Prp24, MESH: RNA Splice Sites, Biology, MESH: Microcephaly, MESH: RNA, Small Nuclear, 03 medical and health sciences, Exon, 0302 clinical medicine, Minor spliceosome, snRNP, MESH: Dwarfism, 030304 developmental biology, MESH: Point Mutation, Genetics, 0303 health sciences, Multidisciplinary, MESH: Humans, urogenital system, MESH: Child, Preschool, Intron, MESH: Osteochondrodysplasias, MESH: Infant, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, MESH: Male, MESH: Cell Line, MESH: Microtubule-Associated Proteins, MESH: Nucleic Acid Conformation, RNA splicing, MESH: Inverted Repeat Sequences, MESH: RNA Splicing, MESH: Female, 030217 neurology & neurosurgery, Small nuclear RNA, MESH: Spliceosomes
Abstract: International audience; The spliceosome, a ribonucleoprotein complex that includes proteins and small nuclear RNAs (snRNAs), catalyzes RNA splicing through intron excision and exon ligation to produce mature messenger RNAs, which, in turn serve as templates for protein translation. We identified four point mutations in the U4atac snRNA component of the minor spliceosome in patients with brain and bone malformations and unexplained postnatal death [microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) or Taybi-Linder syndrome (TALS); Mendelian Inheritance in Man ID no. 210710]. Expression of a subgroup of genes, possibly linked to the disease phenotype, and minor intron splicing were affected in cell lines derived from TALS patients. Our findings demonstrate a crucial role of the minor spliceosome component U4atac snRNA in early human development and postnatal survival.
Published: 2011
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34. Genomic Organization and Nucleotide Sequence of the Coding Region of the Chicken c-Rmil(B-raf-1) Proto-oncogene

Author: Georges Calothy, I. Calogeraki, Alain Eychène, M P Felder, Jean-Vianney Barnier, Maria Marx, CNRS UMR 146 - Institut Curie - Developmental Genetics of Melanocytes (CNRS), Centre National de la Recherche Scientifique (CNRS), and Institut Alfred Fessard
Subjects: MESH: Introns, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Restriction Mapping, MESH: Amino Acid Sequence, MESH: Base Sequence, Proto-Oncogene Mas, Biochemistry, Exon, 0302 clinical medicine, Coding region, MESH: Animals, Lymphocytes, Cloning, Molecular, Conserved Sequence, MESH: Restriction Mapping, Genomic organization, Genetics, Genomic Library, 0303 health sciences, MESH: Conserved Sequence, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, MESH: Chickens, Nucleic acid sequence, MESH: Genomic Library, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Exons, 030220 oncology & carcinogenesis, MESH: DNA Probes, DNA Probes, Molecular Sequence Data, Biophysics, Locus (genetics), Protein Serine-Threonine Kinases, Biology, Quail, MESH: Sequence Homology, Nucleic Acid, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, Proto-Oncogene Proteins, Sequence Homology, Nucleic Acid, Proto-Oncogenes, Animals, Humans, MESH: Cloning, Molecular, Amino Acid Sequence, Molecular Biology, Gene, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Quail, Alternative splicing, Cell Biology, Fibroblasts, Molecular biology, Introns, Proto-Oncogene Proteins c-raf, MESH: Proto-Oncogene Proteins, genomic DNA, MESH: Fibroblasts, MESH: Proto-Oncogenes, MESH: Proto-Oncogene Proteins c-raf, MESH: Lymphocytes, MESH: Exons, Chickens
Abstract: International audience; c-Rmil is the cellular allele of the v-Rmil oncogene, transduced during in vitro passaging of Rous associated virus type 1 in chicken embryonic neuroretina (NR) cells. The c-Rmil proto-oncogene is the avian homolog of the mammalian B-raf gene and belongs to the mil/raf oncogene family of serine/threonine protein kinases. We recently reported that the avian c-Rmil gene encodes two proteins of 94 and 95 kDa, resulting from an alternative splicing mechanism. We describe here the exon-intron organization of the coding region of the chicken c-Rmil locus. We show that c-Rmil proteins are encoded by 19 exons lying within about 100 kbp of genomic DNA. Comparison of the organization of this gene with those of the other mil/raf genes shows strong similarities within three conserved domains previously identified in mil/raf protein kinases. However, c-Rmil contains two additional 5' coding exons that are not present in the other mil/raf genes.
Published: 1993
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35. p53 directly transactivates Δ133p53α, regulating cell fate outcome in response to DNA damage

Author: Anne-Catherine Prats, H. Bernard, David P. Lane, Kenneth Fernandes, Mustapha Aoubala, F. Murray-Zmijewski, Marie P. Khoury, Sébastien Perrier, Jean-Christophe Bourdon, Simon, Marie Francoise, Centre for Oncology and Molecular Medicine, University of Dundee-Inserm-European Associated Laboratory U858, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Transcriptional Activation, Cell cycle checkpoint, MESH: Cell Line, Tumor, DNA damage, MESH: Introns, Molecular Sequence Data, MESH: Genes, p53, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell fate determination, MESH: Base Sequence, MESH: Protein Isoforms, MESH: G1 Phase, Transactivation, MESH: Doxorubicin, Cell Line, Tumor, MESH: Promoter Regions, Genetic, Humans, Protein Isoforms, MESH: Tumor Suppressor Protein p53, Promoter Regions, Genetic, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: DNA Damage, Original Paper, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Apoptosis, G1 Phase, Cell Biology, Cell cycle, Genes, p53, Introns, Cell culture, Doxorubicin, biology.protein, Cancer research, Mdm2, MESH: Transcriptional Activation, Tumor Suppressor Protein p53, DNA Damage
Abstract: International audience; We have previously reported that the human p53 gene encodes at least nine different p53 isoforms, including Δ133p53α, which can modulate p53 transcriptional activity and apoptosis. In this study, we aimed to investigate the regulation of Δ133p53α isoform expression and its physiological role in modulating cell cycle arrest and apoptosis. We report here that in response to a low dose of doxorubicin (which induces cell cycle arrest without promoting apoptosis), p53 directly transactivates the human p53 internal promoter, inducing Δ133p53α protein expression. The induced Δ133p53α then inhibits p53-dependent apoptosis and G1 arrest without inhibiting p53-dependent G2 arrest. Therefore, endogenous Δ133p53α does not exclusively function in a dominant-negative manner toward p53, but differentially regulates cell cycle arrest and apoptosis.
Published: 2010
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36. Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis

Author: Jean Delaunay, Faouzi Baklouti, François Delhommeau, Alain Calender, Madeleine Morinière, Letícia Ribeiro, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Pathologie de la polymérisation des protéines. Substitut du sang et pathologie moléculaire du globule rouge, and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11)
Subjects: MESH: Cytoskeletal Proteins, MESH: Introns, Hereditary elliptocytosis, media_common.quotation_subject, RNA Stability, Nonsense-mediated decay, Nonsense, Nonsense mutation, MESH: Elliptocytosis, Hereditary, MESH: Protein Isoforms, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Protein Isoforms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Codon, Nonsense, RNA, Messenger, Molecular Biology, MESH: RNA, Messenger, 030304 developmental biology, media_common, 0303 health sciences, Mutation, Messenger RNA, MESH: Humans, MESH: Alternative Splicing, Elliptocytosis, Hereditary, Membrane Proteins, MESH: RNA Stability, Cell Biology, Hematology, MRNA stabilization, medicine.disease, Molecular biology, Introns, Alternative Splicing, Cytoskeletal Proteins, Codon, Nonsense, RNA splicing, Molecular Medicine, MESH: Membrane Proteins, 030217 neurology & neurosurgery
Abstract: International audience; We describe a new approach to stabilize nonsense mRNA, based on the inhibition of the NMD mechanism, by combining cycloheximide-mediated inhibition of translation, and caffeine-mediated inhibition of UPF1 phosphorylation. This approach aimed to identify the impact of a 4.1R splicing mutation. This mutation is involved in a partial deficiency of 4.1R in the homozygous state in a patient with hereditary elliptocytosis and a moderated hemolytic anemia. We show that, in addition to two known minor shortened and stable spliceoforms, the mutation activates an intronic cryptic splice site, which results in a nonsense mRNA major isoform, targeted to degradation in intact cells by NMD. This accounts for the main cause of 4.1R partial deficiency. In a general perspective, blocking the NMD mechanism would help to identify a missing isoform, and pave the path for a molecular targeting strategy to circumvent a deleterious splicing pathway in favor of a therapeutic splicing pathway.
Published: 2010
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37. The globin gene family of the cephalochordate amphioxus: implications for chordate globin evolution

Author: Thorsten Burmester, Laurent Kiger, Thomas Hankeln, Serge N. Vinogradov, Georgia Panopoulou, Bettina Ebner, Michael C. Marden, BMC, Ed., Institute of Molecular Genetics, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Substitut du sang et pathologie moléculaire du globule rouge, Institut National de la Santé et de la Recherche Médicale (INSERM), Biocenter Grindel, Zoological Museum-University of Hamburg, and Johannes Gutenberg - Universität Mainz (JGU)
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, MESH: Sequence Analysis, Protein, MESH: Introns, 2R hypothesis, MESH: Amino Acid Sequence, 0302 clinical medicine, Chordata, Nonvertebrate, Sequence Analysis, Protein, Branchiostoma floridae, hemic and lymphatic diseases, MESH: Animals, MESH: Phylogeny, Phylogeny, MESH: Evolution, Molecular, Genetics, Cephalochordate, 0303 health sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, biology, Cytoglobin, Globins, Multigene Family, Research Article, Genome evolution, animal structures, Evolution, MESH: Bayes Theorem, Molecular Sequence Data, Chordate, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Evolution, Molecular, 03 medical and health sciences, QH359-425, MESH: Globins, Animals, MESH: Chordata, Nonvertebrate, Amino Acid Sequence, Globin, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, MESH: Molecular Sequence Data, Bayes Theorem, biology.organism_classification, Introns, Globin fold, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, MESH: Multigene Family, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, 030217 neurology & neurosurgery
Abstract: Background The lancelet amphioxus (Cephalochordata) is a close relative of vertebrates and thus may enhance our understanding of vertebrate gene and genome evolution. In this context, the globins are one of the best studied models for gene family evolution. Previous biochemical studies have demonstrated the presence of an intracellular globin in notochord tissue and myotome of amphioxus, but the corresponding gene has not yet been identified. Genomic resources of Branchiostoma floridae now facilitate the identification, experimental confirmation and molecular evolutionary analysis of its globin gene repertoire. Results We show that B. floridae harbors at least fifteen paralogous globin genes, all of which reveal evidence of gene expression. The protein sequences of twelve globins display the conserved characteristics of a functional globin fold. In phylogenetic analyses, the amphioxus globin BflGb4 forms a common clade with vertebrate neuroglobins, indicating the presence of this nerve globin in cephalochordates. Orthology is corroborated by conserved syntenic linkage of BflGb4 and flanking genes. The kinetics of ligand binding of recombinantly expressed BflGb4 reveals that this globin is hexacoordinated with a high oxygen association rate, thus strongly resembling vertebrate neuroglobin. In addition, possible amphioxus orthologs of the vertebrate globin X lineage and of the myoglobin/cytoglobin/hemoglobin lineage can be identified, including one gene as a candidate for being expressed in notochord tissue. Genomic analyses identify conserved synteny between amphioxus globin-containing regions and the vertebrate β-globin locus, possibly arguing against a late transpositional origin of the β-globin cluster in vertebrates. Some amphioxus globin gene structures exhibit minisatellite-like tandem duplications of intron-exon boundaries ("mirages"), which may serve to explain the creation of novel intron positions within the globin genes. Conclusions The identification of putative orthologs of vertebrate globin variants in the B. floridae genome underlines the importance of cephalochordates for elucidating vertebrate genome evolution. The present study facilitates detailed functional studies of the amphioxus globins in order to trace conserved properties and specific adaptations of respiratory proteins at the base of chordate evolution.
Published: 2010
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38. A Plasmodium falciparum gene coding for a 15-kilodalton antigen expressed in asexual stage parasites, gametocytes and gametes

Author: Jean-Christophe Barale, Thierry Blisnick, Gordon Langsley, David C. Kaslow, Catherine Braun-Breton, T. Ponnudurai, Patricia Barbot, Parasitologie Expérimentale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health [Bethesda] (NIH), University of Nijmegen, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Introns, Genes, Protozoan, Antibodies, Protozoan, Fluorescent Antibody Technique, MESH: Amino Acid Sequence, MESH: Base Sequence, law.invention, MESH: Recombinant Proteins, law, MESH: Animals, Genomic library, MESH: Fluorescent Antibody Technique, ComputingMilieux_MISCELLANEOUS, MESH: Plasmodium falciparum, Polymerase chain reaction, 0303 health sciences, biology, 030302 biochemistry & molecular biology, Exons, MESH: Gene Expression Regulation, Recombinant Proteins, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Genes, Protozoan, Blotting, Western, Molecular Sequence Data, Plasmodium falciparum, MESH: DNA, Protozoan, Antigens, Protozoan, Trypanosoma brucei, Open Reading Frames, 03 medical and health sciences, Complementary DNA, MESH: Gene Library, parasitic diseases, Animals, MESH: Antibodies, Protozoan, MESH: Blotting, Western, Amino Acid Sequence, Molecular Biology, Gene, Gene Library, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, DNA, Protozoan, MESH: Open Reading Frames, biology.organism_classification, Virology, Introns, Open reading frame, genomic DNA, Gene Expression Regulation, Parasitology, MESH: Exons, MESH: Antigens, Protozoan
Abstract: A monoclonal antibody (mAT3) to Trypanosoma brucei glycosyl-phosphatidylinositolphospholipase C (GPI-PLC) which immunoprecipitates Plasmodium falciparum GPI-anchor degrading activities [1,2] was used to screen a 2gtl 1 cDNA expression library. One clone (7.1) was isolated containing a 73-bp insert which was amplified from the 2gtll phage by polymerase chain reaction (PCR) and used to screen asexual stage cDNA, sexual stage cDNA and genomic DNA libraries. In this way the complete gene was obtained and its sequence determined (Fig. 1). A single open reading frame of 372 bp coding for a 15-kDa protein (Agl5) was identified. Comparison of the sexual and asexual stage
Published: 1992
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39. Towards barcode markers in Fungi: an intron map of Ascomycota mitochondria

Author: Graziano Pappadà, Monica Santamaria, Cecilia Saccone, Saverio Vicario, Gaetano Scioscia, Claudio Scazzocchio, Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genetic Markers, Mitochondrial DNA, MESH: Introns, Genes, Fungal, MESH: Ascomycota, Computational biology, MESH: Genetic Markers, Biology, lcsh:Computer applications to medicine. Medical informatics, Barcode, DNA, Mitochondrial, Biochemistry, DNA barcoding, Genome, law.invention, 03 medical and health sciences, Ascomycota, Structural Biology, law, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:QH301-705.5, Molecular Biology, Gene, 030304 developmental biology, Genetics, 0303 health sciences, 030306 microbiology, Applied Mathematics, MESH: DNA, Mitochondrial, Intron, biology.organism_classification, Introns, Computer Science Applications, Proceedings, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, lcsh:Biology (General), Genome, Mitochondrial, MESH: Genome, Fungal, lcsh:R858-859.7, MESH: Genome, Mitochondrial, Genome, Fungal, DNA microarray, MESH: Genes, Fungal
Abstract: Background A standardized and cost-effective molecular identification system is now an urgent need for Fungi owing to their wide involvement in human life quality. In particular the potential use of mitochondrial DNA species markers has been taken in account. Unfortunately, a serious difficulty in the PCR and bioinformatic surveys is due to the presence of mobile introns in almost all the fungal mitochondrial genes. The aim of this work is to verify the incidence of this phenomenon in Ascomycota, testing, at the same time, a new bioinformatic tool for extracting and managing sequence databases annotations, in order to identify the mitochondrial gene regions where introns are missing so as to propose them as species markers. Methods The general trend towards a large occurrence of introns in the mitochondrial genome of Fungi has been confirmed in Ascomycota by an extensive bioinformatic analysis, performed on all the entries concerning 11 mitochondrial protein coding genes and 2 mitochondrial rRNA (ribosomal RNA) specifying genes, belonging to this phylum, available in public nucleotide sequence databases. A new query approach has been developed to retrieve effectively introns information included in these entries. Results After comparing the new query-based approach with a blast-based procedure, with the aim of designing a faithful Ascomycota mitochondrial intron map, the first method appeared clearly the most accurate. Within this map, despite the large pervasiveness of introns, it is possible to distinguish specific regions comprised in several genes, including the full NADH dehydrogenase subunit 6 (ND6) gene, which could be considered as barcode candidates for Ascomycota due to their paucity of introns and to their length, above 400 bp, comparable to the lower end size of the length range of barcodes successfully used in animals. Conclusion The development of the new query system described here would answer the pressing requirement to improve drastically the bioinformatics support to the DNA Barcode Initiative. The large scale investigation of Ascomycota mitochondrial introns performed through this tool, allowing to exclude the introns-rich sequences from the barcode candidates exploration, could be the first step towards a mitochondrial barcoding strategy for these organisms, similar to the standard approach employed in metazoans.
Published: 2009
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40. Polypyrimidine tract binding protein prevents activity of an intronic regulatory element that promotes usage of a composite 3'-terminal exon

Author: Serge Hardy, Hubert Lerivray, Sandra Hamon, Caroline Le Sommer, Agnès Méreau, Vincent Anquetil, De Villemeur, Hervé, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Muscles, MESH: Introns, MESH: Tropomyosin, Tropomyosin, Biochemistry, Xenopus laevis, Exon, MESH: Animals, MESH: Models, Genetic, 0303 health sciences, biology, Muscles, MESH: Alternative Splicing, 030302 biochemistry & molecular biology, Exons, MESH: Gene Expression Regulation, Stop codon, MESH: Polyadenylation, RNA splicing, Female, MESH: Polypyrimidine Tract-Binding Protein, Plasmids, Polypyrimidine Tract-Binding Protein, MESH: Ribonucleases, Polyadenylation, MESH: Oocytes, 03 medical and health sciences, Ribonucleases, Molecular Basis of Cell and Developmental Biology, MESH: Plasmids, MESH: Xenopus laevis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Polypyrimidine tract-binding protein, Enhancer, Molecular Biology, 030304 developmental biology, Messenger RNA, Binding Sites, Models, Genetic, Alternative splicing, Intron, Cell Biology, Molecular biology, Introns, Alternative Splicing, Gene Expression Regulation, MESH: Binding Sites, Oocytes, biology.protein, MESH: Exons, MESH: Female
Abstract: International audience; Alternative splicing of 3'-terminal exons plays a critical role in gene expression by producing mRNA with distinct 3'-untranslated regions that regulate their fate and their expression. The Xenopus alpha-tropomyosin pre-mRNA possesses a composite internal/3'-terminal exon (exon 9A9') that is differentially processed depending on the embryonic tissue. Exon 9A9' is repressed in non-muscle tissue by the polypyrimidine tract binding protein, whereas it is selected as a 3'-terminal or internal exon in myotomal cells and adult striated muscles, respectively. We report here the identification of an intronic regulatory element, designated the upstream terminal exon enhancer (UTE), that is required for the specific usage of exon 9A9' as a 3'-terminal exon in the myotome. We demonstrate that polypyrimidine tract binding protein prevents the activity of UTE in non-muscle cells, whereas a subclass of serine/arginine rich (SR) proteins promotes the selection of exon 9A9' in a UTE-dependent way. Morpholino-targeted blocking of UTE in the embryo strongly reduced the inclusion of exon 9A9' as a 3'-terminal exon in the endogenous mRNA, demonstrating the function of UTE under physiological circumstances. This strategy allowed us to reveal a splicing pathway that generates a mRNA with no in frame stop codon and whose steady-state level is translation-dependent. This result suggests that a non-stop decay mechanism participates in the strict control of the 3'-end processing of the alpha-tropomyosin pre-mRNA.
Published: 2009
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41. Primate-specific spliced PMCHL RNAs are non-protein coding in human and macaque tissues

Author: Audrey Delerue-Audegond, Sandra Schmieder, Marie-Jeanne Arguel, Fleur Darré-Toulemonde, Richard Christen, Jean-Louis Nahon, Laboratoire de physiologie des membranes cellulaires (LPMC), Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)
Subjects: Male, MESH: Protein Precursors, RNA, Untranslated, MESH: Introns, MESH: Amino Acid Sequence, Conserved sequence, MESH: RNA, Untranslated, Exon, 0302 clinical medicine, Testis, MESH: Animals, ORFS, MESH: Phylogeny, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Evolution, Molecular, Phylogeny, Genetics, 0303 health sciences, Hypothalamic Hormones, MESH: Testis, MESH: Macaca, Brain, Exons, 3. Good health, MESH: Primates, RNA splicing, Chromosomes, Human, Pair 5, Research Article, MESH: Chromosomes, Human, Pair 5, Adult, Primates, Lineage (genetic), Evolution, Sequence analysis, RNA Splicing, Molecular Sequence Data, MESH: Sequence Alignment, Biology, Evolution, Molecular, MESH: Brain, 03 medical and health sciences, QH359-425, Animals, Humans, Amino Acid Sequence, Protein Precursors, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Intron, MESH: Adult, MESH: Male, Introns, MESH: Hypothalamic Hormones, Macaca, MESH: RNA Splicing, MESH: Exons, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: [Background] Brain-expressed genes that were created in primate lineage represent obvious candidates to investigate molecular mechanisms that contributed to neural reorganization and emergence of new behavioural functions in Homo sapiens. PMCHL1 arose from retroposition of a pro-melanin-concentrating hormone (PMCH) antisense mRNA on the ancestral human chromosome 5p14 when platyrrhines and catarrhines diverged. Mutations before divergence of hylobatidae led to creation of new exons and finally PMCHL1 duplicated in an ancestor of hominids to generate PMCHL2 at the human chromosome 5q13. A complex pattern of spliced and unspliced PMCHL RNAs were found in human brain and testis., [Results] Several novel spliced PMCHL transcripts have been characterized in human testis and fetal brain, identifying an additional exon and novel splice sites. Sequencing of PMCHL genes in several non-human primates allowed to carry out phylogenetic analyses revealing that the initial retroposition event took place within an intron of the brain cadherin (CDH12) gene, soon after platyrrhine/catarrhine divergence, i.e. 30–35 Mya, and was concomitant with the insertion of an AluSg element. Sequence analysis of the spliced PMCHL transcripts identified only short ORFs of less than 300 bp, with low (VMCH-p8 and protein variants) or no evolutionary conservation. Western blot analyses of human and macaque tissues expressing PMCHL RNA failed to reveal any protein corresponding to VMCH-p8 and protein variants encoded by spliced transcripts., [Conclusion] Our present results improve our knowledge of the gene structure and the evolutionary history of the primate-specific chimeric PMCHL genes. These genes produce multiple spliced transcripts, bearing short, non-conserved and apparently non-translated ORFs that may function as mRNA-like non-coding RNAs., This work was supported by the Centre National de la Recherche Scientifique (CNRS programme OHLL 2002–2004; crédits exceptionnels Biothèque Primate), by a 6th FP EU STREPS/NEST (APES project n° 28594), and by the Agence Nationale de la Recherche (ANR MNP-2008). SS is presently supported by the APES project. FDT was a recipient of a fellowship from the French Education Ministry (Allocation couplée MENRS/ENS). ADA and MJA were supported by the CNRS (crédits exceptionnels Biothèque Primate). MJA was also supported by the MJ Fox Foundation.
Published: 2008
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42. The ribozyme core of group II introns: a structure in want of partners

Author: François Michel, Eric Westhof, Maria Costa, Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Spliceosome, Stereochemistry, MESH: Introns, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biochemistry, 03 medical and health sciences, MESH: RNA, Catalytic, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Catalytic, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, biology, GIR1 branching ribozyme, MESH: Alternative Splicing, 030302 biochemistry & molecular biology, Ribozyme, Group II intron, Introns, Alternative Splicing, RNA splicing, biology.protein, Spliceosomes, Mammalian CPEB3 ribozyme, Hairpin ribozyme, VS ribozyme, MESH: Spliceosomes
Abstract: International audience; Group II introns contain a large ribozyme, which catalyzes self-splicing, and the coding sequence of a reverse transcriptase, the function of which is to cooperate with the ribozyme to achieve genomic mobility. Despite its lack of substrates for both steps of the splicing process, the crystal structure of a group II ribozyme reveals the location of two metal ions most likely to be involved in catalysis; the RNA structure that binds to these ions results from the bending of a local motif by the folding of the rest of the ribozyme. The stage is now set to determine where the intron-encoded protein binds to its partner and whether the spliceosome uses a counterpart of the group II catalytic center to excise nuclear pre-messenger introns.
Published: 2008
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43. Multiplex allele-specific fluorescent PCR for haplotyping the IVS8 (TG)m(T)n locus in the CFTR gene

Author: Costa, Catherine, Costa, Jean-Marc, Martin, Josiane, Boissier, Brigitte, Goossens, Michel, Girodon, Emmanuelle, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Moléculaire, Hôpital américain, and Guellaen, Georges
Subjects: MESH: Cystic Fibrosis Transmembrane Conductance Regulator, MESH: Humans, MESH: Introns, MESH: Alleles, MESH: Polymerase Chain Reaction, MESH: Haplotypes, (TG)m(T)n, T5 variant, haplotyping, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CBAVD, CFTR, MESH: Spectrometry, Fluorescence
Abstract: International audience; BACKGROUND: Precise genotyping of the intron 8 poly(TG) and poly(T) tracts of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is of clinical relevance in CFTR pathology. The (TG)(m) locus influences the penetrance of the (T)(5) allele, which may be associated with male infertility by congenital bilateral absence of the vas deferens (CBAVD) or other CFTR-related disorders (CFTR-RD), in particular in the context of (TG)(12) and (TG)(13). Simple and accurate genotyping of both loci should thus be routinely offered in laboratories. METHODS: We designed a new single test method relying on multiplex allele-specific fluorescent PCR: (T)(5)-, (T)(7)-, and (T)(9)-specific primers, labeled with different fluorophores, in combination with a common primer. Each fluorescent PCR product was identified on a capillary sequencer by its fluorescence color, specific for (T)(n), and size, indicative of the (TG) length. We first validated the assay in 2 different laboratories on 52 DNA samples with already known genotypes. We then evaluated the method prospectively, compared with sequencing, on 62 samples from healthy individuals and 108 samples from patients with CBAVD or other CFTR-RDs. RESULTS: We observed a 100% match in both validation steps. Results found in CBAVD and CFTR-RD patients are in keeping with data in the literature. CONCLUSIONS: The assay proved to be simple, rapid, and accurate for single-test (TG)(m)(T)(n) genotyping and suited for analysis in clinical laboratories.
Published: 2008
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44. Multiplex allele-specific fluorescent PCR for haplotyping the IVS8 (TG)m(T)n locus in the CFTR gene.: Direct haplotyping of CFTR IVS8 (TG)m(T)n

Author: J.P. Martin, Catherine Costa, Michel Goossens, Jean-Marc Costa, Brigitte Boissier, Emmanuelle Girodon, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Moléculaire, and Hôpital américain
Subjects: MESH: Introns, Clinical Biochemistry, Cystic Fibrosis Transmembrane Conductance Regulator, Locus (genetics), Biology, (TG)m(T)n, T5 variant, Polymerase Chain Reaction, Article, law.invention, 03 medical and health sciences, law, Genotype, Multiplex polymerase chain reaction, Humans, Multiplex, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, CFTR, Genotyping, Polymerase chain reaction, Alleles, 030304 developmental biology, Genetics, MESH: Cystic Fibrosis Transmembrane Conductance Regulator, 0303 health sciences, MESH: Humans, MESH: Alleles, 030305 genetics & heredity, Biochemistry (medical), MESH: Polymerase Chain Reaction, MESH: Haplotypes, Molecular biology, haplotyping, Introns, 3. Good health, Spectrometry, Fluorescence, Haplotypes, CBAVD, Primer (molecular biology), MESH: Spectrometry, Fluorescence
Abstract: Background: Precise genotyping of the intron 8 poly(TG) and poly(T) tracts of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is of clinical relevance in CFTR pathology. The (TG)m locus influences the penetrance of the (T)5 allele, which may be associated with male infertility by congenital bilateral absence of the vas deferens (CBAVD) or other CFTR-related disorders (CFTR-RD), in particular in the context of (TG)12 and (TG)13. Simple and accurate genotyping of both loci should thus be routinely offered in laboratories. Methods: We designed a new single test method relying on multiplex allele-specific fluorescent PCR: (T)5-, (T)7-, and (T)9-specific primers, labeled with different fluorophores, in combination with a common primer. Each fluorescent PCR product was identified on a capillary sequencer by its fluorescence color, specific for (T)n, and size, indicative of the (TG) length. We first validated the assay in 2 different laboratories on 52 DNA samples with already known genotypes. We then evaluated the method prospectively, compared with sequencing, on 62 samples from healthy individuals and 108 samples from patients with CBAVD or other CFTR-RDs. Results: We observed a 100% match in both validation steps. Results found in CBAVD and CFTR-RD patients are in keeping with data in the literature. Conclusions: The assay proved to be simple, rapid, and accurate for single-test (TG)m(T)n genotyping and suited for analysis in clinical laboratories.
Published: 2008
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45. A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism

Author: Thierry Brue, Frédérique Albarel, Rachel Reynaud, Alexandru Saveanu, Raja Brauner, Marie-Helene Quentien, M. El Kholy, Alain Enjalbert, Anne-Marie Guedj, N. Kaffel, Anne Barlier, Frederic Castinetti, M. Amin, A. Buffin, 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), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), 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), and Université de la Méditerranée - Aix-Marseille 2 - Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH : Transcription Factors, MESH: Introns, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Electrophoretic Mobility Shift Assay, MESH : Genotype, Hypopituitarism, medicine.disease_cause, MESH: Hypopituitarism, Biochemistry, MESH: Genotype, 0302 clinical medicine, Endocrinology, MESH : Female, MESH : Homeodomain Proteins, Pituitary stalk, 0303 health sciences, Mutation, MESH: Middle Aged, MESH : Hypopituitarism, MESH: Transcription Factors, Middle Aged, MESH : Adult, Pedigree, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 3. Good health, MESH : Phenotype, Phenotype, medicine.anatomical_structure, Sella turcica, MESH : Electrophoretic Mobility Shift Assay, Female, MESH : Mutation, Adult, medicine.medical_specialty, MESH: Mutation, Genotype, Somatotropic cell, MESH: Pedigree, MESH : Male, LIM-Homeodomain Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, MESH: Phenotype, MESH : Introns, 03 medical and health sciences, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Posterior pituitary, Internal medicine, MESH: Homeodomain Proteins, medicine, Humans, MESH : Middle Aged, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Homeodomain Proteins, MESH: Humans, Biochemistry (medical), MESH : Humans, Heterozygote advantage, MESH: Adult, medicine.disease, Introns, MESH: Male, MESH : Pedigree, MESH: Electrophoretic Mobility Shift Assay, MESH: Female, Transcription Factors
Abstract: International audience; CONTEXT: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone deficiency. SUBJECTS AND METHODS: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations. RESULTS: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients' phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters. CONCLUSIONS: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.
Published: 2008
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46. Molecular characterization and chromosomal assignment of equine cartilage derived retinoic acid sensitive protein (CD-RAP)/melanoma inhibitory activity (MIA)

Author: Lise C. Berg, Xavier Mata, Preben D. Thomsen, Department of Veterinary and Animal Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Génétique Animale et Biologie Intégrative (GABI), and Institut National de la Recherche Agronomique (INRA)-AgroParisTech
Subjects: MESH: Extracellular Matrix Proteins, MESH: Introns, Retinoic acid, Gene Expression, MESH: Base Sequence, chemistry.chemical_compound, Exon, Gene expression, MESH: Animals, Promoter Regions, Genetic, Peptide sequence, Extracellular Matrix Proteins, 0303 health sciences, 030302 biochemistry & molecular biology, Chromosome Mapping, Exons, General Medicine, 3. Good health, medicine.anatomical_structure, MESH: Gene Expression, RNA Splicing, Molecular Sequence Data, Tretinoin, Biology, Chromosomes, Chondrocyte, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Horses, MESH: Horses, Gene, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Tretinoin, Base Sequence, Melanoma inhibitory activity, Alternative splicing, Molecular biology, Introns, Cartilage, chemistry, MESH: Cartilage, MESH: Chromosomes, MESH: RNA Splicing, MESH: Chromosome Mapping, MESH: Exons
Abstract: International audience; Cartilage-derived retinoic acid sensitive protein (CD-RAP) also known as melanoma inhibitory activity (MIA) has already been established as a marker for chondrocyte differentiation and a number of cancerous conditions in humans. Studies have also shown that CD-RAP/MIA is a potential marker of joint disease. The objective of this study was to characterize the equine CD-RAP/MIA gene and thus make it available as a marker in cartilage research and clinical studies. Gene analysis revealed that the equine gene (GenBank accession no. EF679787) consists of four exons and three introns, and the homology to the human gene is 90% for the translated region. The upstream sequence includes regulatory elements and putative transcription factor binding sites previously described in the human and murine promoter regions. The deduced amino acid sequence consists of 130 aa including a signal peptide of 23 aa, and has a 91% identity to the human protein. Using radiation hybrid mapping, the CD-RAP/MIA gene was localized to the p arm of equine chromosome 10 (ECA10p), which is in accordance with prediction based on the current human-equine comparative map. Gene expression studies showed expression of CD-RAP/MIA mRNA in articular cartilage and chondrocytes from horses with no signs of joint disease. The expression decreased as the cells dedifferentiated in monolayer culture. We also identified an equine CD-RAP/MIA splice variant similar to that reported in humans. The CD-RAP/MIA protein was detected in equine synovial fluid, serum and culture medium from chondrocyte cultures. In conclusion, CD-RAP/MIA is expressed in equine cartilage and chondrocytes, and the protein can be detected in equine serum, synovial fluid and in culture medium from chondrocyte cultures. The equine gene and resulting protein share great homology with the human gene, making future studies on CD-RAP/MIAs potential as a marker in joint disease possible using the equine joint as a model.
Published: 2008
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47. Proteasomal degradation restricts the nuclear lifespan of AID

Author: Jean-Claude Weill, Sandra K. Weller, Said Aoufouchi, Ahmad Faili, Orietta D’Orlando, Claude-Agnès Reynaud, Carole Zober, Aoufouchi, Said, Développement du Systeme 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), Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine - University of Udine [Italie], Ligue Nationale contre le Cancer, European Commission, 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: Transcription, Genetic, MESH: Introns, MESH: Cell Cycle, Cytidine, Cytosine Deaminase, Mice, 0302 clinical medicine, Ubiquitin, Genes, Reporter, Protein biosynthesis, Activation-induced (cytidine) deaminase, Immunology and Allergy, MESH: Animals, MESH: Immunoglobulin G, 0303 health sciences, biology, MESH: Kinetics, MESH: Proteasome Endopeptidase Complex, MESH: Gene Expression Regulation, Enzymologic, Cell Cycle, Articles, Exons, Cytidine deaminase, Cell cycle, medicine.anatomical_structure, Biochemistry, MESH: Protein Biosynthesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cytidine, MESH: Cell Nucleus, Proteasome Endopeptidase Complex, MESH: Enzyme Activation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunoprecipitation, MESH: Mice, Transgenic, Immunology, Mice, Transgenic, ubiquitination, Article, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, medicine, Animals, MESH: Mice, 030304 developmental biology, Cell Nucleus, MESH: Transcription, Genetic, MESH: Cytosine Deaminase, MESH: Genes, Reporter, Cell Biology, proteasome degradation, Introns, Enzyme Activation, Kinetics, Cell nucleus, Proteasome, Immunoglobulin G, Protein Biosynthesis, biology.protein, aicda, MESH: Exons, 030215 immunology
Abstract: International audience; Activation-induced cytidine deaminase (AID) initiates all postrearrangement processes that diversify the immunoglobulin repertoire by specific deamination of cytidines at the immunoglobulin (Ig) locus. As uncontrolled expression of AID is potentially mutagenic, different types of regulation, particularly nucleocytoplasmic shuttling, restrict the likelihood of AID-deoxyribonucleic acid encounters. We studied additional mechanisms of regulation affecting the stability of the AID protein. No modulation of protein accumulation according to the cell cycle was observed in a Burkitt's lymphoma cell line. In contrast, the half-life of AID was markedly reduced in the nucleus, and this destabilization was accompanied by a polyubiquitination that was revealed in the presence of proteasome inhibitors. The same compartment-specific degradation was observed in activated mouse B cells, and also in a non-B cell line. No specific lysine residues could be linked to this degradation, so it remains unclear whether polyubiquitination proceeds through several alternatives sites or through the protein N terminus. The nuclear-restricted form of AID displayed enhanced mutagenicity at both Ig and non-Ig loci, most notably at TP53, suggesting that modulation of nuclear AID content through proteasomal degradation may represent another level of control of AID activity.
Published: 2008
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48. Transcriptional and epigenetic regulation of the integrin collagen receptor locus ITGA1-PELO-ITGA2

Author: Thomas J. Kunicki, Yann Cheli, Mei Chang, Diane J. Nugent, Beatrice Jacquelin, Sachiko Kanaji, The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), and University of California-University of California
Subjects: MESH: Hydroxamic Acids, Transcription, Genetic, MESH: Introns, Megakaryocyte differentiation, [SDV]Life Sciences [q-bio], Integrin alpha1, Integrin alpha2, Hydroxamic Acids, Biochemistry, Epigenesis, Genetic, Collagen receptor, MESH: DNA Methylation, Structural Biology, MESH: Epigenesis, Genetic, Enzyme Inhibitors, Promoter Regions, Genetic, 0303 health sciences, 030302 biochemistry & molecular biology, Nuclear Proteins, Cell Differentiation, Methylation, MESH: Thrombopoietin, MESH: Megakaryocytes, MESH: Leukocytes, Mononuclear, Thrombopoietin, CpG site, MESH: Enzyme Inhibitors, DNA methylation, Azacitidine, Chromosomes, Human, Pair 5, Megakaryocytes, MESH: Cell Differentiation, MESH: Chromosomes, Human, Pair 5, MESH: Integrin alpha1, Quantitative Trait Loci, Biophysics, MESH: Integrin alpha2, MESH: Azacitidine, Biology, Decitabine, MESH: Integrin alpha1beta1, Article, Integrin alpha1beta1, 03 medical and health sciences, Epigenetics of physical exercise, Serum response factor, MESH: Promoter Regions, Genetic, Genetics, Humans, Epigenetics, 030304 developmental biology, MESH: K562 Cells, MESH: Humans, MESH: Decitabine, MESH: Transcription, Genetic, DNA Methylation, Molecular biology, Introns, MESH: Quantitative Trait Loci, MESH: HeLa Cells, Leukocytes, Mononuclear, K562 Cells, MESH: Nuclear Proteins, HeLa Cells
Abstract: International audience; The integrin collagen receptor locus on human chromosome 5q11.2 includes the integrin genes ITGA1 and ITGA2, and the cell cycle regulation gene PELO, embedded within ITGA1 intron 1. ITGA1 contains a CArG box that is bound by serum response factor (SRF), while PELO contains two Sp1 binding elements. A comparison of mRNA levels in megakaryocytic (MK) and non-megakaryocytic (non-MK) cell lines and an analysis of the transcriptional activity of promoter-LUC reporter gene constructs in transfected cells revealed that ITGA1 is selectively suppressed in the MK lineage. Sodium bisulfite genomic sequencing established that a CpG-rich ITGA1 promoter region (-209/+115) is fully methylated at 19 CpG sites in MK cells that do not express alpha1beta1, but completely demethylated in expressing cells. In vitro methylation of ITGA1 suppresses transcription, while treatment of megakaryocytic cells with 5-aza-2'-deoxycytidine, but not Trichostatin A, resulted in de novo expression of ITGA1. During thrombopoietin-induced in vitro differentiation of primary human cord blood mononuclear cells into megakaryocytes, we observed rapid, progressive CpG methylation of ITGA1, but not PELO or ITGA2. Thus, selective CpG methylation of the ITGA1 promoter is a specific feature of alpha1beta1 regulation that coincides with the initiation of megakaryocyte differentiation.
Published: 2007
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49. The usage of alternative splice sites in Mus musculus synaptotagmin-like 2 gene is modulated by cyclosporin A and FK506 in T-lymphocytes

Author: Paolo Truffa-Bachi, Laurent Mascarell, Jean Kanellopoulos, Rodolphe Auger, Biologie des Populations Lymphocytaires, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: MESH: Introns, T-Lymphocytes, Sequence Homology, MESH: Amino Acid Sequence, MESH: Base Sequence, Lymphocyte Activation, MESH: Cyclosporine, Mice, Exon, Cyclosporin a, Protein Isoforms, MESH: Animals, Cells, Cultured, 0303 health sciences, Genome, Splice site mutation, MESH: Alternative Splicing, 030302 biochemistry & molecular biology, Exons, MESH: Gene Expression Regulation, Cyclosporine, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Membrane Proteins, MESH: Calcineurin, MESH: Cells, Cultured, Gene isoform, Calcineurin Inhibitors, Molecular Sequence Data, Immunology, Biology, MESH: Open Reading Fram, Tacrolimus, Open Reading Frames, 03 medical and health sciences, Animals, MESH: Genome, Amino Acid Sequence, RNA, Messenger, MESH: Lymphocyte Activation, Molecular Biology, Gene, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Intron, Membrane Proteins, Promoter, Molecular biology, Introns, Alternative Splicing, Open reading frame, Gene Expression Regulation, RNA Splice Sites, MESH: Exons
Abstract: Cyclosporin-A and FK506 block the calcineurin activity preventing the transcription of genes sharing NFAT-like binding sequences in their promoter region. We presently show that activation of murine T-cells in presence of these immunosuppressors results in the up-regulation of the synaptotagmin-like 2 gene. However, of the four known isoforms, only mRNAs encoding the a and b isoforms accumulate. Two previously undected isoforms, each characterized by the retention of an intron, were found. The first, Slp2-e, includes exon 8, intron 8 and exon 9. The second, Slp2-f, is composed of exon 7, intron 7 and exon 8. Slp2-f has an open reading frame coding for a putative protein of 1229 amino acids sharing 47% identities with the human breast-associated antigen, SGA-72 M. In addition to the well-documented modulation of gene transcription, the two immunosuppressors also play a role in the choice of alternative splice sites on murine Slp2 pre-mRNA.
Published: 2007
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50. Bsr, a nuclear-retained RNA with monoallelic expression

Author: Jérôme Cavaillé, Maud Marques, Eugenia Basyuk, Edouard Bertrand, Virginie Marty, Hélène Royo, Laboratoire de biologie moléculaire eucaryote du CNRS ( LBME ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherches sur la Cognition Animale [Toulouse] ( CRCA ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Departament Geodinàmica i Geofísica, Facultat de Geologia, Laboratoire de Physique Statistique de l'ENS ( LPS ), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris ( FRDPENS ), Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Colloïdes et Matériaux Divisés ( LCMD ), ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Liquides Ioniques et Interfaces Chargées ( LI2C ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Ecole Nationale de la Santé Publique ( ENSP ), École des Hautes Études en Santé Publique [EHESP] ( EHESP ), Centre de recherches Paul Pascal ( CRPP ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-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)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), 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), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-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), Département de biologie [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), Laboratoire de Physique Statistique de l'ENS (LPS), Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Colloïdes et Matériaux Divisés (LCMD), Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Liquides Ioniques et Interfaces Chargées (LI2C), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Ecole Nationale de la Santé Publique (ENSP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre de recherches Paul Pascal (CRPP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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 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), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris)
Subjects: MESH: Hydroxamic Acids, RNA, Untranslated, MESH : RNA, Messenger, MESH: Introns, RNA Stability, Hydroxamic Acids, RNA Transport, MESH: RNA, Untranslated, 0302 clinical medicine, MESH: RNA Transport, Transcription (biology), Gene cluster, MESH : RNA, MESH: Animals, MESH : Cell Nucleus Structures, MESH : Female, MESH : RNA Transport, Genetics, 0303 health sciences, MESH : Cell Nucleus, MESH : Rats, MESH: RNA Stability, Articles, MESH : RNA Stability, Non-coding RNA, medicine.anatomical_structure, RNA splicing, Female, MESH : RNA Splicing, MESH: Cell Nucleus, MESH : RNA, Untranslated, MESH: Rats, RNA Splicing, MESH: Cytoplasmic Granules, Biology, Cytoplasmic Granules, MESH : Rats, Wistar, MESH : Introns, 03 medical and health sciences, MESH: RNA, MESH : Fibroblasts, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Cell Nucleus Structures, RNA, Messenger, Rats, Wistar, Molecular Biology, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Alleles, MESH: RNA, Messenger, 030304 developmental biology, Cell Nucleus, MESH : Hydroxamic Acids, MESH: Alleles, MESH : Cytoplasmic Granules, Intron, RNA, MESH: Rats, Wistar, Cell Biology, Fibroblasts, Cell Nucleus Structures, Introns, Rats, Cell nucleus, MESH: Fibroblasts, MESH : Animals, MESH: RNA Splicing, MESH : Alleles, MESH: Female, 030217 neurology & neurosurgery
Abstract: The imprinted Dlk1-Gtl2 and Prader-Willi syndrome (PWS) regions are characterized by a complex noncoding transcription unit spanning arrays of tandemly repeated C/D RNA genes. These noncoding RNAs (ncRNAs) are thought to play an essential but still poorly understood role. To better understand the intracellular fate of these large ncRNAs, fluorescence in situ hybridization was carried out at the rat Dlk1-Gtl2 domain. This locus contains a ∼100-kb-long gene cluster comprising 86 homologous RBII-36 C/D RNA gene copies, all of them intron-encoded within the ncRNA gene Bsr. Here, we demonstrate that the Bsr gene is monoallelically expressed in primary rat embryonic fibroblasts as well as in hypothalamic neurons and yields a large amount of unspliced and spliced RNAs at the transcription site, mostly as elongated RNA signals. Surprisingly, spliced Bsr RNAs released from the transcription site mainly concentrate as numerous, stable nuclear foci that do not colocalize with any known subnuclear structures. On drug treatments, a fraction of Bsr RNA relocalizes to the cytoplasm and associates with stress granules (SGs), but not with P-bodies, pointing to a potential link between SGs and the metabolism of ncRNA. Thus, Bsr might represent a novel type of nuclear-retained transcript.
Published: 2007
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