Descriptor: "MESH: Alleles" / Topic: medicine - Searchworks@Jio Institute Digital Library Search Results

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179 results on '"MESH: Alleles"'

1. Evidence of mosaicism in SPAST variant carriers in four French families

Author: William Camu, Guillaume Banneau, Samia Ait Said, Eric LeGuern, Christel Depienne, Bophara Kol, Caroline Rooryck, Clarisse Scherer-Gagou, Giovanni Stevanin, Laurène Tissier, Perrine Pennamen, Bénédicte Héron, Cyril Goizet, Marine Guillaud-Bataille, Chloé Angelini, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe hospitalier Pellegrin, Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Duisbourg-Essen, Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and Institut Fédératif de Biologie (IFB) - Hôpital Purpan
Subjects: Male, MESH: Alleles, Child, Comparative Genomic Hybridization, Female, France, Gene Frequency, Heterozygote, High-Throughput Nucleotide Sequencing, Spastin, Medizin, Brief Communication, Spastic Paraplegias, 03 medical and health sciences, Genetic etiology, Genetics, Spastic, Medicine, Humans, Diagnostic laboratory, Genetics (clinical), Alleles, 0303 health sciences, business.industry, Mosaicism, Spastic Paraplegia, Hereditary, 030305 genetics & heredity, Homozygote, Middle Aged, Penetrance, 3. Good health, Pedigree, nervous system diseases, Phenotype, Somatic mosaicism, Mutation, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Hereditary spastic paraplegias (HSP) are heterogeneous disorders, with more than 70 causative genes. Variants in SPAST are the most frequent genetic etiology and are responsible for spastic paraplegia type 4 (SPG4). Age at onset can vary, even between patients from the same family, and incomplete penetrance is described. Somatic mosaicism is extremely rare with only three patients reported in the literature. We report here SPAST mosaic variants in four unrelated patients. We confirm that mosaicism in SPAST is a very rare event with only four identified cases on more than 300 patients with a SPAST variant previously described by our clinical diagnostic laboratory.
Published: 2021

2. A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

Author: Henry Houlden, Thomas Haaf, Pratishtha Varshney, Christian Beetz, Hamid Galehdari, Lucy A Dunbar, Alireza Sedaghat, Richard J.H. Smith, Michael R. Bowl, Aziz El-Amraoui, Kevin T. Booth, David Murphy, Neda Mazaheri, Sandrine Vitry, Kumar N. Alagramam, Ben Fowler, Shruthi VijayKumar, Aboulfazl Rad, Hela Azaiez, Cassidy Petree, Barbara Vona, Sheng-Jia Lin, Gholamreza Shariati, Reza Maroofian, Franz Rüschendorf, Gaurav K. Varshney, EL-AMRAOUI, Aziz, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie - - HearInNoise2017 - ANR-17-CE16-0017 - AAPG2017 - VALID, Julius-Maximilians-Universität Würzburg (JMU), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Shahid Chamran University of Ahvaz (SCU), Oklahoma Medical Research Foundation (OMRF), MRC Harwell Institute [UK], University College of London [London] (UCL), University of Iowa [Iowa City], Harvard Medical School [Boston] (HMS), Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, Pathophysiology and Therapy (DSP), Sorbonne Université (SU)-Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, CENTOGENE AG, Case Western Reserve University [Cleveland], Ahvaz Jundishapur University of Medical Sciences (AJUMS), Narges Medical Genetics and Prenatal Diagnostics, Open Access funding enabled and organized by Projekt DEAL. This work was supported by Intramural Funding (fortüne) at the University of Tübingen (2545-1-0 to BV), the Ministry of Science, Research and Art Baden-Württemberg (to BV), the Medical Research Council (MC_UP_1503/2 to MRB), ANR light4deaf (ANR-15-RHUS-0001), HearInNoise (ANR-17-CE16-0017), LHW-stiftung to AE), and a grant from NIH/COBRE GM103636 (Project 3), the Presbyterian Health Foundation (PHF) Grant to GKV. This study was funded in part by NIDCDs R01s DC002842 and DC012049 to RJS and T32 GM007748 to KTB. LAD is a Medical Research Council DPhil student (1774724)., We would like to extend our gratitude to the family for their participation. We thank Dr. Caroline Lekszas, Dr. Daniel Liedtke, and Dr. Indrajit Nanda from the Institute of Human Genetics at the University of Würzburg for their technical expertise., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-17-CE16-0017,HearInNoise,Surdité d'apparition tardive et progressive: de la physiopathologie à la thérapie(2017), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Carver College of Medicine, University of Iowa, Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University Hospitals of Cleveland, This work was supported by Intramural Funding (fortüne) at the University of Tübingen (2545-1-0 to B.V.), the Ministry of Science, Research and Art Baden-Württemberg (to B.V.), the Medical Research Council (MC_UP_1503/2 to M.R.B), ANR light4deaf (ANR-15-RHUS-0001), HearInNoise (ANR-17-CE16-0017), LHW-stiftung (to A.E.), and a grant from NIH/COBRE GM103636 (Project 3), the Presbyterian Health Foundation (PHF) Grant to G.K.V. This study was funded in part by NIDCDs R01s DC002842 and DC012049 to R.J.S and T32 GM007748 to K.T.B. L.A.D is a Medical Research Council DPhil student (1774724)., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Déficits Sensoriels Progressifs, Pathophysiologie et Thérapie / Progressive Sensory Disorders, PathoPhysiology and Therapy (DSP)
Subjects: Male, Tetraspanins, [SDV]Life Sciences [q-bio], Gene Expression, MESH: Base Sequence, Consanguinity, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, Zebrafish, Genetics (clinical), Exome sequencing, Original Investigation, Genetics, 0303 health sciences, Chromosome Mapping, Disease gene identification, MESH: Amino Acid Substitution, Stop codon, Pedigree, [SDV] Life Sciences [q-bio], Female, Sensorineural hearing loss, MESH: Membrane Proteins, Chromosomes, Human, Pair 4, medicine.symptom, Adult, MESH: Chromosomes, Human, Pair 4, MESH: Gene Expression, Hearing loss, MESH: Pedigree, Hearing Loss, Sensorineural, Genes, Recessive, Locus (genetics), Biology, MESH: Hair Cells, Auditory, Inner, 03 medical and health sciences, MESH: Whole Exome Sequencing, Exome Sequencing, medicine, otorhinolaryngologic diseases, Animals, Humans, Point Mutation, ddc:610, MESH: Zebrafish, MESH: Mice, Alleles, MESH: Genes, Recessive, 030304 developmental biology, MESH: Point Mutation, MESH: Consanguinity, Hair Cells, Auditory, Inner, MESH: Humans, Base Sequence, MESH: Alleles, Intron, Membrane Proteins, MESH: Adult, medicine.disease, MESH: Male, Amino Acid Substitution, MESH: Hearing Loss, Sensorineural, Cardiovascular and Metabolic Diseases, MESH: Chromosome Mapping, MESH: Tetraspanins, MESH: Female, 030217 neurology & neurosurgery
Abstract: Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Published: 2021

3. The Leishmania donovani species complex: A new insight into taxonomy☆

Author: Cristina Ballart, Fouad El Baidouri, Anna Fernández-Arévalo, Montserrat Gállego, Patrick Lami, Silvia Tebar, Francine Pratlong, Laurence Lachaud, Alba Abras, Christophe Ravel, Carme Muñoz, Universitat de Barcelona (UB), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), University of Hawai‘i [Mānoa] (UHM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), and Universitat de Girona (UdG)
Subjects: 0301 basic medicine, MALDI-TOF, Genotype, 030231 tropical medicine, Leishmania donovani complex, MESH: Dogs, MESH: Genotype, MESH: Phlebotomus, 03 medical and health sciences, 0302 clinical medicine, Dogs, parasitic diseases, medicine, Animals, Humans, Sequencing, MESH: Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Genetic variability, MESH: Genetic Variation, Allele, Leishmania infantum, Alleles, Taxonomy, Genetics, MESH: Humans, MESH: Leishmania donovani, biology, MESH: Alleles, Genetic Variation, biology.organism_classification, medicine.disease, MESH: Leishmania infantum, Sandfly, 030104 developmental biology, Infectious Diseases, Visceral leishmaniasis, MESH: Leishmaniasis, Visceral, Phlebotomus, Leishmaniasis, Visceral, Parasitology, Taxonomy (biology), MLEE, Leishmania donovani
Abstract: Among the 20 or so Leishmania spp. described as pathogenic for humans, those of the Leishmania donovani complex are the exclusive causative agents of systemic and fatal visceral leishmaniasis. Although well studied, the complex is taxonomically controversial, which hampers clinical and epidemiological research. In this work, we analysed 56 Leishmania strains previously identified as L. donovani, Leishmania archibaldi or Leishmania infantum, isolated from humans, dogs and sandfly vectors throughout their distribution area. The strains were submitted to biochemical and genetic analyses and the resulting data were compared for congruence. Our results show: i) a partial concordance between biochemical and genetic-based data, ii) very limited genetic variability within the L. donovani complex, iii) footprints of frequent genetic exchange along an east-west gradient, marked by a widespread diffusion of alleles across the geographical range, and iv) a large-scale geographical spreading of a few genotypes. From a taxonomic point of view, considering the absence of relevant terminology in existing classes, the L. dono-vani complex could be treated as a single entity. (C) 2020 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.
Published: 2020

4. The role of rare compound heterozygous events in autism spectrum disorder

Author: Thomas Bourgeron, Alistair T. Pagnamenta, Jeremy R. Parr, Louise Gallagher, Christine M. Freitag, Jacob A. S. Vorstman, Sean Ennis, Isaac J. Nijman, Fabrice Colas, Kristel R. van Eijk, Bochao Danae Lin, Jurjen J. Luykx, Jelena Medic, Sabine M. Klauck, Elena Maestrini, Astrid M. Vicente, Richard Anney, Guiomar Oliveira, Elena Bacchelli, Hilary Coon, Andreas G. Chiocchetti, William J. Brands, Utrecht University [Utrecht], Henan University, Kaifeng, Newcastle University [Newcastle], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Goethe-Universität Frankfurt am Main, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of Utah School of Medicine [Salt Lake City], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), Centro Hospitalar e Universitário [Coimbra], University of Oxford [Oxford], Trinity College Dublin, University College Dublin [Dublin] (UCD), Cardiff University, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), GGNet Mental Health [Apeldoorn, The Netherlands], The Hospital for sick children [Toronto] (SickKids), University of Toronto, This study has been funded by the Dutch Brain Foundation (Hersenstichting Nederland) to JV., Lin B.D., Colas F., Nijman I.J., Medic J., Brands W., Parr J.R., van Eijk K.R., Klauck S.M., Chiocchetti A.G., Freitag C.M., Maestrini E., Bacchelli E., Coon H., Vicente A., Oliveira G., Pagnamenta A.T., Gallagher L., Ennis S., Anney R., Bourgeron T., Luykx J.J., Vorstman J., Henan University, University of Oxford, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Proband, DNA Copy Number Variations, Autism Spectrum Disorder, Autism, Biology, Compound heterozygosity, ASD, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Biological Psychiatry, Alleles, MESH: Autism Spectrum Disorder, Genetics, Comparative genomics, MESH: Humans, MESH: Alleles, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Genetic Predisposition to Disease, Autism spectrum disorders, medicine.disease, Penetrance, Autism Spectrum Disorders, Autism, CNVs, Deletions, SNVs, Compound Heterozygosity, Targeted Sequencing, Psychiatry and Mental health, 030104 developmental biology, Autism spectrum disorder, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: DNA Copy Number Variations, 030217 neurology & neurosurgery
Abstract: The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X2 = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X2 = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10−5). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
Published: 2020

5. Malaria and Dengue Mosquito Vectors from Lao PDR Show a Lack of the rdl Mutant Allele Responsible for Cyclodiene Insecticide Resistance

Author: Susannah Lechmere, Omobolanle H Abdullateef, Phoutmany Thammavong, Natalie M Portwood, Safina Khadam, Chloé Boer, Somsanith Chonephetsarath, Rosie Longstreeth, Paul T. Brey, Anna E Jacob, Nursu C Kuyucu, Wlaa Ali, Phonesavanh Luangamath, Jordan Forward, Andrew K. Jones, Santi Maithaviphet, Sébastien Marcombe, Somphat Nilaxay, Zuhal Rahmani, Simone Nambanya, Hayato Kakinuma, Natasha Brown, Joseph Hawkins, Penelope J Saverton, Madeleine Smee, Khaitong Lakeomany, Gabriela Stieger, Nothasin Phommavanh, Institut Pasteur du Laos, Réseau International des Instituts Pasteur (RIIP), Oxford Brookes University, Ministry of Health [Laos], and The mosquito collections, rearing and identification work was carried out within the framework of the MALVEC research project funded by the 5% initiative from the French Ministry of Foreign Affairs and International Development. For extraction and amplification of DNA from mosquitoes, funding was provided by Oxford Brookes University.
Subjects: Insecticides, MESH: Dengue, medicine.disease_cause, Dengue fever, Dengue, chemistry.chemical_compound, 0302 clinical medicine, Aedes, MESH: Insect Proteins, MESH: Animals, 0303 health sciences, Mutation, biology, Anopheles, dieldrin, insecticide resistance, MESH: Aedes, 3. Good health, Infectious Diseases, Laos, Insect Proteins, MESH: Mosquito Vectors, Aedes albopictus, MESH: Mutation, 030231 tropical medicine, MESH: Malaria, mosquito, Aedes aegypti, Mosquito Vectors, MESH: Anopheles, 03 medical and health sciences, Dieldrin, GABA receptor, parasitic diseases, medicine, Animals, MESH: Insecticide Resistance, Alleles, 030304 developmental biology, General Veterinary, MESH: Alleles, fungi, medicine.disease, biology.organism_classification, Virology, Malaria, MESH: Insecticides, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, chemistry, MESH: Laos, Insect Science, MESH: Dieldrin, Parasitology
Abstract: The gamma-aminobutyric acid (GABA) receptor, RDL, plays important roles in neuronal signaling and is the target of highly effective insecticides. A mutation in RDL, commonly A296S, underlies resistance to several insecticides such as cyclodienes. Even though the use of cyclodienes has been banned, the occurrence of mutations substituting A296 is notably high in mosquitoes from several countries. Here, we report a survey investigating the prevalence of the Rdl mutant allele in mosquitoes from Laos, a country where mosquito-borne diseases such as malaria and dengue fever are health concerns. Anopheles and Aedes mosquitoes were collected from 12 provinces in Laos. Adult bioassays on Aedes aegypti (Linnaeus) (Diptera: Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae) showed that all the populations tested were susceptible to dieldrin (4%) following WHO protocols. Exon 7 from a total of 791 mosquitoes was sequenced to identify the amino acid encoded for at 296 of RDL. Only one of these mosquitoes, Anopheles maculatus rampae Harbach and Somboon (Diptera: Culicidae) from Attapeu, carried the mutant allele being heterozygous for A296S. We therefore found a general lack of the Rdl mutant allele indicating that mosquitoes from Laos are not exposed to insecticides that act on the GABA receptor compared to mosquitoes in several other countries. Identifying the prevalence of the Rdl mutation may help inform the potential use of alternative insecticides that act on the GABA receptor should there be a need to replace pyrethroids in order to prevent/manage resistance.
Published: 2020

6. MPL mutations in essential thrombocythemia uncover a common path of activation with eltrombopag dependent on W491

Author: Jean-Marc Zini, Serge Carillo, Benjamin Papoular, Stefan N. Constantinescu, Emilie Leroy, Bruno Cassinat, Ilyas Chachoua, Leila N. Varghese, Steven O. Smith, Gabriel Levy, Jean-Philippe Defour, De Duve Institute, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research, Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), Cliniques Universitaires Saint-Luc [Bruxelles], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De Duve Institute, Université Catholique de Louvain, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), UCL - SSS/DDUV/SIGN - Cell signalling, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Service d'hématologie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
Subjects: Immunology, Mutant, Eltrombopag, Mutagenesis (molecular biology technique), MESH: Receptors, Thrombopoietin / genetics, Signal Transduction / drug effects, Thrombocythemia, Essential / diagnosis, Thrombocythemia, Essential / genetics, Thrombocythemia, Essential / metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Alleles, Amino Acid Substitution, Benzoates / pharmacology, Cell Line, Genetic Association Studies, Genetic Predisposition to Disease, medicine.disease_cause, Biochemistry, Benzoates, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Protein-fragment complementation assay, medicine, Humans, Alleles, 030304 developmental biology, Thrombopoietin receptor, 0303 health sciences, Mutation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Phenotype, Transmembrane protein, 3. Good health, Cell biology, Hydrazines, chemistry, 030220 oncology & carcinogenesis, Pyrazoles, MESH: Humans, Hydrazines / pharmacology, Pyrazoles / pharmacology, Receptors, Thrombopoietin / agonists, Receptors, Thrombopoietin, Signal Transduction, Thrombocythemia, Essential
Abstract: Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate a truncated TpoR mutant, which lacks the extracellular domain, indicating these mutations act on the transmembrane (TM) cytosolic domain. Using a protein complementation assay, we showed that L498W and H499C strongly drive dimerization of TpoR. Activation by tryptophan substitution is exquisitely specific for position 498. Using structure-guided mutagenesis, we identified upstream amino acid W491 as a key residue required for activation by L498W or canonical activating mutations such as S505N and W515K, as well as by eltrombopag. Structural data point to a common dimerization and activation path for TpoR via its TM domain that is shared between the small-molecule agonist eltrombopag and canonical and novel activating TpoR mutations that all depend on W491, a potentially accessible extracellular residue that could become a target for therapeutic intervention.
Published: 2020

7. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Author: Neuray, C., Maroofian, R., Scala, M., Sultan, T., Pai, G. S., Mojarrad, M., Khashab, H. E., Deholl, L., Yue, W., Alsaif, H. S., Zanetti, M. N., Bello, O., Person, R., Eslahi, A., Khazaei, Z., Feizabadi, M. H., Efthymiou, S., El-Bassyouni, H. T., Soliman, D. R., Tekes, S., Ozer, L., Baltaci, V., Khan, S., Beetz, C., Amr, K. S., Salpietro, V., Jamshidi, Y., Alkuraya, F. S., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Synaps, Group, Di Rosa, G., Aguennouz, M., Goraya, J. S., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Sherifa, H., Neuray C., Maroofian R., Scala M., Sultan T., Pai G.S., Mojarrad M., Khashab H.E., deHoll L., Yue W., Alsaif H.S., Zanetti M.N., Bello O., Person R., Eslahi A., Khazaei Z., Feizabadi M.H., Efthymiou S., El-Bassyouni H.T., Soliman D.R., Tekes S., Ozer L., Baltaci V., Khan S., Beetz C., Amr K.S., Salpietro V., Jamshidi Y., Alkuraya F.S., Houlden H., Mangano S., Dicle Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı, Tekeş, Selahattin, University College of London [London] (UCL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), University of Genoa (UNIGE), IRCCS Istituto Giannina Gaslini [Genoa, Italy], Children's Hospital [Lahore], Institute of Child Health [Lahore], Medical University of South Carolina [Charleston] (MUSC), Mashhad University of Medical Sciences, Ain Shams University (ASU), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Khorasan Razavi Agricultural and Natural Resources Research and Education Center, National Research Centre [Cairo, Egypt], Benha University (BU), Dicle University, CENTOGENE AG, University of London [London], King Faisal Specialist Hospital [Riyadh, Saudi Arabia] (Research Centre), and SYNaPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Gabriella Di Rosa, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D Ferrari, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimi Zollo, Gali Heimer, Yves A Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa
Subjects: Male, 0301 basic medicine, Glutamate decarboxylase, Malalties cerebrals, Neurotransmissors, Neurodevelopmental delay, Epilepsy, 0302 clinical medicine, MESH: Child, Age of Onset, Child, cleft palate, GAD1, AcademicSubjects/SCI01870, Glutamate Decarboxylase, Glutamate receptor, Muscle weakness, purl.org/becyt/ford/3.1 [https], Neurotransmitters, MESH: Infant, Hypotonia, muscle weakne, Cleft palate, MESH: Epilepsy, Child, Preschool, Muscle Hypotonia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], purl.org/becyt/ford/3 [https], Female, Brain diseases, Abnormalities, medicine.symptom, Multiple, medicine.drug, epilepsy, muscle weakness, neurodevelopmental delay, MESH: Glutamate Decarboxylase, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Mutation, MESH: Age of Onset, Biology, Inhibitory postsynaptic potential, GAD1, cleft palate, epilepsy, muscle weakness, neurodevelopmental delay, gamma-Aminobutyric acid, 03 medical and health sciences, Excitatory synapse, Internal medicine, medicine, Humans, Abnormalities, Multiple, Preschool, Alleles, MESH: Neurodevelopmental Disorders, MESH: Humans, MESH: Muscle Hypotonia, MESH: Alleles, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, Epilèpsia, Editor's Choice, 030104 developmental biology, Endocrinology, Neurodevelopmental Disorders, Mutation, AcademicSubjects/MED00310, Neurology (clinical), MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Reports
Abstract: Mice lacking GAD1 show neonatal mortality, but the human phenotype associated with GAD1 disruption is poorly characterized. Neuray et al. describe six patients with biallelic GAD1 mutations, presenting with early-infantile onset epilepsy, neurodevelopmental delay, muscle weakness and non-CNS manifestations., Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.
Published: 2020

8. Identification of a functional FADS1 3′UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels

Author: Xavier Hermant, Amandine Flaig, Dominique Cottel, Gilbert Briand, Brigitte Laillet, Chantal Simon, Aline Meirhaeghe, Marie-Adélaïde Bout, Julie Dumont, Dominique Arveiler, Aline Wagner, Jean Dallongeville, Charlotte Delay, Jean-Bernard Ruidavets, Jimena Luque-Bedregal, Jean Ferrières, Philippe Amouyel, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hormonologie, Métabolisme-Nutrition & Oncologie (HMNO), Département de Biochimie et Biologie Moléculaire-Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Deutsches Zentrum für Luft- und Raumfahrt (DLR), Faculté de Médecine, EA 3430 Laboratoire d’Epidémiologie et de Santé Publique, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Epidémiologie, Economie de la Santé et Santé Publique, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire, INRA Clermont-Ferrand (INRA Clermont), Institut National de la Recherche Agronomique (INRA), U 744, Laboratoire d’Epidémiologie et de Santé Publique, Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (Inserm)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, The MONA LISA study was supported by a grant from the Agence Nationale de la Recherche (ANR-05-PNRA-018), the Institut National de Veille Sanitaire, INSERM, and a grant from Pfizer. This work was funded by the Conseil Régional du Nord-Pas-de-Calais and the European Regional Development Fund as part of the CPER Cardio-diabete program (contract 09220016)., ANR-05-PNRA-0018,MONA LISA-NUT,MONA LISA – NUT (MOnitoring NAtionaL du rISque Artériel – NUTrition). Relations entre les habitudes alimentaires et la prévalence des facteurs de risque cardiovasculaireans trois régions françaises.(2005), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Fattouma Bourguiba [Monastir] (HFB), ANR-05-PNRA-0018,MONA LISA-NUT,MONA LISA – NUT (MOnitoring NAtionaL du rISque Artériel – NUTrition). Relations entre les habitudes alimentaires et la prévalence des facteurs de risque cardiovasculaire dans trois régions françaises.(2005), Université Lille Nord de France (COMUE)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (Inserm)
Subjects: Fatty Acid Desaturases, Male, 0301 basic medicine, Linkage disequilibrium, Erythrocytes, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, MESH: Base Sequence, 030204 cardiovascular system & hematology, MESH: Multigene Family/genetics, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, Medicine, Genetic epidemiology, 3' Untranslated Regions, MESH: Aged, Genetics, chemistry.chemical_classification, MESH: Middle Aged, Nutrition and Dietetics, Gene polymorphism, Hep G2 Cells, Middle Aged, Phenotype, Multigene Family, Female, MESH: MicroRNAs/genetics, Cardiology and Cardiovascular Medicine, MESH: Computational Biology, Polyunsaturated fatty acid, Adult, MESH: Erythrocytes/metabolism, Desaturase, FADS1, FADS2, Down-Regulation, MESH: Hep G2 Cells, MiRNA binding, MESH: Phenotype, Polymorphism, Single Nucleotide, MESH: Down-Regulation/genetics, 03 medical and health sciences, Fatty Acids, Omega-6, Functional variant, Internal Medicine, Humans, MESH: Fatty Acids, Omega-6/metabolism, Alleles, miRNA, Aged, MESH: Humans, Base Sequence, MESH: Fatty Acid Desaturases/genetics, business.industry, MESH: Alleles, Haplotype, MESH: Polymorphism, Single Nucleotide, Computational Biology, MESH: Adult, MESH: 3' Untranslated Regions/genetics, MESH: Male, Minor allele frequency, MicroRNAs, 030104 developmental biology, chemistry, Polyunsaturated fatty acids, business, MESH: Female
Abstract: International audience; BACKGROUND: Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Delta 5- and Delta 6-desaturases (encoded by the FADS] and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS)-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. OBJECTIVE: Here, we sought to identify the functional variant(s) within the FADS gene cluster. METHODS: To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. RESULTS: The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-gamma-linolenic acid and lower levels of arachidonic acid, suggesting a lower Delta 5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. CONCLUSION: This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes.
Published: 2018

9. A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer

Author: Didier Busso, Lluis Quintana-Murci, Paul-Henri Romeo, Juliette Hamroune, Anaïs Assouvie, Germain Rousselet, Maxime Rotival, Laboratoire de Recherche sur la Réparation et la Transcription dans les Cellules Souches (LRTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), U 1016/ UMR 8104 Institut Cochin, Plate-Forme Séquençage et Génomique (Genom'IC), Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), La Ligue contre le cancer, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Collège de France - Chaire Génomique humaine et évolution, and Quintana-Murci, lluis
Subjects: Lipopolysaccharides, Cancer Research, Myeloid, Single Nucleotide Polymorphisms, Gene Expression, QH426-470, MESH: Mice, Knockout, Biochemistry, Monocytes, Mice, White Blood Cells, 0302 clinical medicine, Transcription (biology), Animal Cells, Gene expression, Medicine and Health Sciences, MESH: Animals, Myeloid Cells, Promoter Regions, Genetic, Genetics (clinical), Cells, Cultured, Mice, Knockout, 0303 health sciences, Mammalian Genomics, MESH: Polymorphism, Single Nucleotide, MESH: Transcription Factors, Genomics, MESH: Gene Expression Regulation, 3. Good health, Enzymes, medicine.anatomical_structure, Enhancer Elements, Genetic, Cellular Types, Oxidoreductases, Luciferase, MESH: Cells, Cultured, Research Article, MESH: Blood Buffy Coat, Immune Cells, Primary Cell Culture, Quantitative Trait Loci, Immunology, Bone Marrow Cells, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, MESH: CCAAT-Enhancer-Binding Protein-beta, MESH: Primary Cell Culture, 03 medical and health sciences, MESH: Promoter Regions, Genetic, DNA-binding proteins, medicine, Genetics, Animals, Humans, Point Mutation, Gene Regulation, Allele, Enhancer, Molecular Biology, Transcription factor, Gene, MESH: Mice, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, MESH: Point Mutation, MESH: Humans, Blood Cells, MESH: Interferon-beta, MESH: Alleles, CCAAT-Enhancer-Binding Protein-beta, Macrophages, Biology and Life Sciences, Proteins, Interferon-beta, Cell Biology, TRIM33, Molecular biology, MESH: Myeloid Cells, MESH: Quantitative Trait Loci, Regulatory Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Gene Expression Regulation, Animal Genomics, Blood Buffy Coat, Enzymology, MESH: Enhancer Elements, Genetic, MESH: Lipopolysaccharides, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Interferon β (IFN-β) is a cytokine that induces a global antiviral proteome, and regulates the adaptive immune response to infections and tumors. Its effects strongly depend on its level and timing of expression. Therefore, the transcription of its coding gene IFNB1 is strictly controlled. We have previously shown that in mice, the TRIM33 protein restrains Ifnb1 transcription in activated myeloid cells through an upstream inhibitory sequence called ICE. Here, we show that the deregulation of Ifnb1 expression observed in murine Trim33-/- macrophages correlates with abnormal looping of both ICE and the Ifnb1 gene to a 100 kb downstream region overlapping the Ptplad2/Hacd4 gene. This region is a predicted myeloid super-enhancer in which we could characterize 3 myeloid-specific active enhancers, one of which (E5) increases the response of the Ifnb1 promoter to activation. In humans, the orthologous region contains several single nucleotide polymorphisms (SNPs) known to be associated with decreased expression of IFNB1 in activated monocytes, and loops to the IFNB1 gene. The strongest association is found for the rs12553564 SNP, located in the E5 orthologous region. The minor allele of rs12553564 disrupts a conserved C/EBP-β binding motif, prevents binding of C/EBP-β, and abolishes the activation-induced enhancer activity of E5. Altogether, these results establish a link between a genetic variant preventing binding of a transcription factor and a higher order phenotype, and suggest that the frequent minor allele (around 30% worldwide) might be associated with phenotypes regulated by IFN-β expression in myeloid cells., Author summary Genome-wide association studies identify multiple genetic variants associated with higher order phenotypes. Pinpointing the causative variant and understanding its molecular mode of action is a complex task. Using a murine model of interferon-β transcriptional deregulation, we characterize a super-enhancer controlling Ifnb1 expression in myeloid cells. The most active enhancer of this locus is conserved in humans, but presents a frequent variant found in around 30% of the population worldwide. This variant prevents binding of the C/EBP-β transcription factor, and is associated with decreased expression of IFNB1 in activated monocytes. When mimicked in the murine enhancer, it abolishes its inducible enhancer activity. Our results describe the molecular link between a point mutation and a cellular phenotype that could influence clinical situations.
Published: 2019

10. Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations

Author: Merih Berberoğlu, Régis Coutant, Şenay Savaş Erdeve, Cécile Brachet, Caroline Thalassinos, Frédéric Brioude, Michel Polak, Erdal Kurnaz, Sabrina Belkacem, Claudine Heinrichs, Aude Soleyan, Zeynep Şıklar, Nathalie Collot, Philippe Chanson, Jean-Claude Carel, Zehra Aycan, Marie-Laure Sobrier, Serge Amselem, Géraldine Viot, Noureddine Kaffel, Stanislas Lyonnet, Philippe Duquesnoy, Eliane Khallouf, Marie Legendre, Enzo Cohen, Soumeya Fedala, Sophie Rose, Florence Dastot, Frédérique Gatelais, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lamine Debaghine [Alger, Algérie] (HLD), Centre Hospitalier Universitaire Bab El Oued [Alger, Algérie] (CHU Bab El Oued), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Hôtel-Dieu de France (HDF), Université Saint-Joseph de Beyrouth (USJ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpitaux Universitaires Paris Centre (CHU Paris Centre), Hôpital Robert Debré, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Universitaire des Enfants Reine Fabiola [Brussels, Belgium]. (HUERF), Complexe Médical Multidisciplinaire [Sfax, Tunisia] (C2M), Ankara University School of Medicine [Turkey], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Dupuis, Christine, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service de Génétique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Universitaire des Enfants Reine Fabiola, Université libre de Bruxelles (ULB), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Division of Paediatric Endocrinology, Dr Sami Ulus Woman Health, Children Research Hospital, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Children's University Hospital Queen Fabiola [Bruxelles, Belgium], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Receptors, Neuropeptide, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Amino Acid Sequence, medicine.disease_cause, molecular epidemiology, MESH: Genotype, Exon, Receptors, Pituitary Hormone-Regulating Hormone, Cyclic AMP, IGHD, MESH: Human Growth Hormone, Missense mutation, MESH: DNA Mutational Analysis, Idiopathic Isolated Growth Hormone Deficiency, Genetics (clinical), genotype‐phenotype correlation, MESH: Cyclic AMP, MESH: Genetic Association Studies, Genetics, 0303 health sciences, Mutation, Human Growth Hormone, MESH: Receptors, Neuropeptide, 030305 genetics & heredity, MESH: Genetic Predisposition to Disease, MESH: Amino Acid Substitution, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], functional studies, Female, MESH: Mutation, Genotype, MESH: Pedigree, Genetic counseling, GHRHR, Biology, genotype-phenotype correlation, MESH: Dwarfism, Pituitary, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Dwarfism, Pituitary, Gene, Alleles, Genetic Association Studies, 030304 developmental biology, MESH: Humans, Molecular epidemiology, MESH: Receptors, Pituitary Hormone-Regulating Hormone, MESH: Alleles, MESH: Male, Amino Acid Substitution, MESH: Female
Abstract: International audience; Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.
Published: 2019

11. Control of progression towards liver fibrosis and hepatocellular carcinoma by SOCS3 polymorphisms in chronic HCV-infected patients

Author: Pascal Pineau, Hanane Salih Alj, Imane Zaidane, Rachid Saile, Fatima Zahra Jadid, Soumaya Benjelloun, Hajar Chihab, Sanaa Tazi, Sayeh Ezzikouri, Agnès Marchio, Raouia Elfihry, Wafaa Badre, Kamal Marhoum El Filali, Mohammed Tahiri, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), Université Hassan II [Casablanca] (UH2MC), CHU Ibn Rochd [Casablanca], Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), MARCHIO, Agnes, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Liver Cirrhosis, Male, 0301 basic medicine, Oncology, Cirrhosis, Genetic Linkage, Hepacivirus, medicine.disease_cause, Linkage Disequilibrium, MESH: Genotype, Liver disease, Gene Frequency, MESH: Liver Neoplasms, MESH: Hepacivirus, SOCS3, MESH: Carcinoma, Hepatocellular, MESH: Polymorphism, Single Nucleotide, Liver Neoplasms, MESH: Genetic Predisposition to Disease, Viral Load, MESH: Case-Control Studies, MESH: Gene Expression Regulation, 3. Good health, HCV infection, MESH: Hepatitis C, Chronic, Infectious Diseases, Real-time polymerase chain reaction, MESH: Linkage Disequilibrium, MESH: Suppressor of Cytokine Signaling 3 Protein, Hepatocellular carcinoma, Disease Progression, Female, MESH: Disease Progression, MESH: Liver Cirrhosis, MESH: Viral Load, Microbiology (medical), medicine.medical_specialty, Carcinoma, Hepatocellular, Genotype, Hepatitis C virus, MESH: Genetic Linkage, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, Microbiology, 03 medical and health sciences, Insulin resistance, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, MESH: Polymorphism, Genetic, Genetics, medicine, MESH: Gene Frequency, Humans, Genetic Predisposition to Disease, Polymorphism, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Polymorphism, Genetic, MESH: Humans, MESH: Alleles, mRNA expression, Hepatitis C, Chronic, medicine.disease, MESH: Male, 030104 developmental biology, Gene Expression Regulation, Suppressor of Cytokine Signaling 3 Protein, Case-Control Studies, MESH: Biomarkers, MESH: Female, Biomarkers
Abstract: Chronic Hepatitis C is one of the most important risk factors of liver cirrhosis and hepatocellular carcinoma. Before reaching these ultimate steps, insulin resistance triggered by hepatitis C virus infection is known to participate in the progression of liver disease. The present study aims to investigate the influence of two functional polymorphisms on SOCS3 mRNA expression and on the outcomes of CHC progression in a North African context.In this case-control study, 601 Moroccan subjects composed of 200 healthy controls, 101 resolvers and 300 patients with persistent HCV infection including 95 mild chronic hepatitis, 131 Advanced Liver Diseases and 74 HCC were enrolled. They were genotyped for the 4874 A/G (rs4969170) and A + 930- G (rs4969168) SOCS3 variants using TaqMan SNPs assays. SOCS3 mRNA expression was assessed using Real Time PCR technique.Logistic regression analysis showed that variation at rs4969168 was associated with spontaneous clearance of HCV (P 0.05). In addition, minor allele frequencies were significantly higher in AdLD patients when compared to the mCHC group both for rs4969168 (P = 7.0 E-04) and rs4969170 (P = 4.0 E-05). A significant association between haplotype and liver disease progression was also found. Moreover, SOCS3 mRNA was significantly more expressed in peripheral leukocytes from patients with HCC than in those from mCHC. Finally, rs4969170 was significantly associated with LDL-lipoprotein (P = 0.04), total cholesterol (P = 5.0 E-04), and higher fasting glucose levels (P = 0.005) in patients with persistent HCV infection.Our results underline the importance of the functional SOCS3 polymorphisms in the modulation of CHC progression and suggest their contribution to HCC development by affecting its mRNA expression and perturbing key metabolic parameters.
Published: 2018

12. The pathophysiology of polymyalgia rheumatica, small pieces of a big puzzle

Author: Divi Cornec, Guillermo Carvajal Alegria, Valérie Devauchelle-Pensec, Sara Boukhlal, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), CCSD, Accord Elsevier, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: musculoskeletal diseases, 0301 basic medicine, Aging, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Giant Cell Arteritis, education, Immunology, Human leukocyte antigen, CD8-Positive T-Lymphocytes, Proinflammatory cytokine, Polymyalgia rheumatica, 03 medical and health sciences, 0302 clinical medicine, MESH: B-Lymphocytes, medicine, HLA-DR, Homeostasis, Humans, Immunology and Allergy, In patient, Alleles, MESH: HLA-DRB1 Chains, 030203 arthritis & rheumatology, B-Lymphocytes, B cell, MESH: Humans, Interleukin-6, business.industry, MESH: Alleles, T cell, MESH: Giant Cell Arteritis, medicine.disease, MESH: CD8-Positive T-Lymphocytes, MESH: Interleukin-6, Pathophysiology, 3. Good health, [SDV] Life Sciences [q-bio], Giant cell arteritis, 030104 developmental biology, MESH: Homeostasis, MESH: Polymyalgia Rheumatica, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, HLA-DRB1 Chains
Abstract: International audience; Polymyalgia rheumatica (PMR) is a frequent rheumatic condition among people over 50 years of age. Despite its frequent association with giant cell arteritis (GCA), PMR can be isolated. Its pathophysiology is poorly understood. Nevertheless, many studies are ongoing; 98 studies are currently referenced in ClinicalTrials.org involving several conventional and targeted therapies. In this review, we synthetize the current knowledge about PMR pathophysiology according to genetic and immunogenetic, immunologic, antibody and aging data. Immunogenetic data are mainly related to the HLA system and the association between the HLA-DRB1 and PMR. Few studies are also about immunogenetics of proinflammatory interleukins (i.e. IL-6). The decrease of CD8+Tcells and the strong increase of IL-6 where the main elements of PMR's pathophysiology until the recent years. The disturbance of B cell homeostasis, the search for IL-6 secretion by the innate immune system, the role of aging, are new elements revealed by recent studies. Aging might be a key element to consider as PMR occurs in patients over 50 years of age. Aging may act by the increased susceptibility to infections, by immunological modifications or hormonal disturbances. The role of the cellular infiltration around the joints remains a crucial question. Only a handful of studies described this infiltration. Finally, this review reveals the gaps in available data and suggests new leads and in-depth studies for further research on PMR pathophysiology.
Published: 2020

13. A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients

Author: Khaoula Ben-Farhat, Monia Khemiri, Zohra Fitouri, Sihem Barsaoui, Najla Mekki, Meriem Ben-Ali, Selim Abdelmoula, Mohamed-Neji Guediche, M. R. Barbouche, Samir Boukthir, Saber Hamami, Imen Ben-Mustapha, Amel Ben-Chehida, Jalel Chemli, Karen Rouault, Beya Larguèche, Université de Tunis El Manar (UTM), Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté de Médecine de Tunis, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pédiatrique [Hôpital Fattouma Bourguiba - Monastir], CHU Fattouma Bourguiba [Monastir] (HFB), Department of Pediatrics [Tunis], Hôpital La Rabta [Tunis], Béchir Hamza Children's Hospital, and Hôpital Universitaire Sahloul (CHU Sahloul)
Subjects: Male, 0301 basic medicine, Neutrophils, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Granulomatous Disease, Chronic, medicine.disease_cause, Severity of Illness Index, Consanguinity, 0302 clinical medicine, Chronic granulomatous disease, MESH: Child, Immunology and Allergy, MESH: NADPH Oxidases/genetics, MESH: DNA Mutational Analysis, Child, MESH: Neutrophils/metabolism, MESH: Genetic Association Studies, Genetics, Mutation, MESH: Infant, Founder Effect, 3. Good health, Phenotype, Child, Preschool, 030220 oncology & carcinogenesis, Female, MESH: Tunisia, NCF2 gene, MESH: Alleles, MESH: Enzyme Activation, Tunisia, Immunology, Biology, MESH: Phenotype, 03 medical and health sciences, MESH: Genetic Predisposition to Disease, MESH: Severity of Illness Index, MESH: Founder Effect, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, Alleles, Genetic Association Studies, MESH: Consanguinity, MESH: Granulomatous Disease, Chronic/diagnosis, MESH: Humans, MESH: Granulomatous Disease, Chronic/genetics, MESH: Child, Preschool, Haplotype, Infant, NADPH Oxidases, MESH: Granulomatous Disease, Chronic/metabolism, MESH: Haplotypes, medicine.disease, MESH: Male, Enzyme Activation, 030104 developmental biology, Haplotypes, Genetic marker, MESH: Neutrophils/immunology, MESH: Mutation, MESH: NADPH Oxidases/metabolism, MESH: Female, Founder effect
Abstract: International audience; Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.
Published: 2016

14. Enterobacteria and host resistance to infection

Author: Alanna Crouse, Eugene Kang, Xavier Montagutelli, Samantha Gruenheid, Lucie Chevallier, Navoun Silué, François-Xavier Campbell-Valois, Ashwag Alzahrani, Danielle Malo, Stéphanie M. Pontier, McGill University Research Centre on Complex Traits [Montreal] (MRCCT), McGill University = Université McGill [Montréal, Canada], Biologie du système neuromusculaire - Biology of the neuromuscular system [Maisons-Alfort] (BNMS - Team 10), École nationale vétérinaire d'Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris], Department of Chemistry and Biomolecular Science, University of Ottawa, University of Ottawa [Ottawa], Funding for this work was supported by the Canadian Institutes of Health Research grants to S.G. (Grant No. MOP 133580) and to D.M. (Grant No. MOP133700), by Genome Canada and Génome Québec to S.G. and D.M., by the National Science and Engineering Research Council of Canada (NSERC, Grant No. RGPIN-2016-05587) and the Faculty of Science of the University of Ottawa to F.X.C.V. E.K. was supported by studentships from the Faculty of Medicine, McGill University, A.A. by a scholarship from the King Abdullah Scholarship program supported by the Saudi Arabia Cultural Bureau and N.S. by a studentship from the NSERC CREATE program TECHNOMISE., L.C. and X.M. are grateful to Christian Demeure for useful discussions on Y. pestis pathogenesis and mouse models., MONTAGUTELLI, Xavier, École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Salmonella, Quantitative Trait Loci, 030106 microbiology, MESH: Disease Susceptibility, MESH: Disease Resistance, [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, Yersinia, medicine.disease_cause, Microbiology, 03 medical and health sciences, MESH: Enterobacteriaceae, Enterobacteriaceae, Escherichia, Flora (microbiology), Genetics, medicine, Animals, Humans, Shigella, MESH: Animals, MESH: Enterobacteriaceae Infections, Alleles, Disease Resistance, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, biology, MESH: Alleles, MESH: Host-Pathogen Interactions, Enterobacteriaceae Infections, biology.organism_classification, MESH: Quantitative Trait Loci, 3. Good health, Disease Models, Animal, 030104 developmental biology, Host-Pathogen Interactions, Disease Susceptibility, MESH: Disease Models, Animal, Bacteria
Abstract: International audience; Enterobacteriaceae are a large family of Gram-negative, non-spore-forming bacteria. Although many species exist as part of the natural flora of animals including humans, some members are associated with both intestinal and extraintestinal diseases. In this review, we focus on members of this family that have important roles in human disease: Salmonella, Escherichia, Shigella, and Yersinia, providing a brief overview of the disease caused by these bacteria, highlighting the contribution of animal models to our understanding of their pathogenesis and of host genetic determinants involved in susceptibility or resistance to infection.
Published: 2018

15. Unusual association of a unique CAG interruption in 5′ of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism

Author: Yann Péréon, Stéphanie Tomé, Céline Dogan, Jean-Paul Bonnefont, Alexis Bertrand, Elodie Dandelot, David Geneviève, Guillaume Bassez, Geneviève Gourdon, Marie Simon, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre de Référence des maladies neuromusculaires rares Nantes-Angers, Service des Explorations Fonctionnelles, Centre hospitalier universitaire de Nantes (CHU Nantes), École de sages-femmes - Caen (ESF Caen), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Service de génétique moléculaire [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôtel-Dieu de Nantes, UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], 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), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Contraction (grammar), MESH: Pedigree, [SDV]Life Sciences [q-bio], High variability, MESH: Myotonic Dystrophy / genetics, Pedigree chart, 030105 genetics & heredity, Biology, Triplet repeat instability, Myotonic dystrophy, Myotonin-Protein Kinase, 03 medical and health sciences, MESH: Trinucleotide Repeat Expansion / genetics, Genetics, medicine, Humans, Myotonic Dystrophy, Genetic Predisposition to Disease, Genetics (clinical), Alleles, CTG contractions and 5' single CAG interruption, ComputingMilieux_MISCELLANEOUS, MESH: Myotonic Dystrophy / physiopathology, Ctg repeat, MESH: Humans, Mosaicism, Myotonic dystrophy type 1, MESH: Alleles, medicine.disease, MESH: Male, Pedigree, Somatic mosaicism, MESH: Genetic predisposition to disease, Female, MESH: Mosaicism, Trinucleotide Repeat Expansion, MESH: Female
Abstract: International audience; Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5' of the CTG expansion in one family, whereas multiple 5' CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet-prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3' of the interruptions for both families.
Published: 2018

16. Evidence of CD4+ T cell-mediated immune pressure on the Hepatitis C virus genome

Author: Spyros A. Kalams, M. Azim Ansari, Simon Mallal, Andri Rauch, E Barnes, Louise Barnett, Ian James, Anne Plauzolles, Mark A. Pilkinton, Karen Fitzmaurice, Mina John, Elouise Gaylard, Heidi E. Drummer, Silvana Gaudieri, Pooja Deshpande, Dermot Kelleher, Katja Pfafferott, Andrew Lucas, Michaela Lucas, Wyatt J. McDonnell, Cody A. Chastain, Shahzma Merani, Vincent Pedergnana, Paul Klenerman, Amy Prosser, The University of Western Australia (UWA), Murdoch University, Bern University Hospital [Berne] (Inselspital), University of Bern, University of Oxford, John Radcliffe Hospital [Oxford University Hospital], University of Alberta, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Monash university, University of Melbourne, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), The Wellcome Trust Centre for Human Genetics [Oxford], Royal Perth Hospital, Fiona Stanley Hospital [Murdoch], Trinity College Dublin, and University of British Columbia (UBC)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Hepacivirus, Epitopes, T-Lymphocyte, CD8-Positive T-Lymphocytes, Viral Nonstructural Proteins, medicine.disease_cause, MESH: Genotype, Cohort Studies, Genotype, HLA-DQ beta-Chains, MESH: Hepacivirus, MESH: Cohort Studies, MESH: HLA-DRB1 Chains, Multidisciplinary, biology, MESH: CD4-Positive T-Lymphocytes, virus diseases, MESH: CD8-Positive T-Lymphocytes, MESH: Gene Expression Regulation, MESH: Hepatitis C, Chronic, 3. Good health, medicine.anatomical_structure, Host-Pathogen Interactions, Medicine, MESH: Genome, Viral, MESH: Mutation, Science, T cell, Hepatitis C virus, 610 Medicine & health, Human leukocyte antigen, Genome, Viral, Virus, Article, MESH: Epitopes, T-Lymphocyte, 03 medical and health sciences, Immune system, medicine, Humans, Alleles, MESH: Humans, MESH: Alleles, MESH: Host-Pathogen Interactions, Hepatitis C, Chronic, MESH: HLA-DQ beta-Chains, biology.organism_classification, Virology, digestive system diseases, 030104 developmental biology, Gene Expression Regulation, Mutation, MESH: Viral Nonstructural Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, CD8, HLA-DRB1 Chains
Abstract: Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8+ T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4+ T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4+ T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01; Fisher’s exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4+ T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4+ T cell epitopes.
Published: 2018

17. FOXE3 mutations: Genotype-phenotype correlations

Author: H. Dollfus, Gilles Morin, J. C. Kaplan, Christine Francannet, Hélène Colineaux, Nicola K. Ragge, Daphné Lehalle, Nicolas Chassaing, Julie Plaisancié, Patrick Calvas, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Oxford Brookes University, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Genetics in Ophthalmology (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Génétique Clinique et Oncogénétique, Centre Hospitalier Universitaire d'Amiens Picardie, Amiens, France, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: 0301 basic medicine, Male, MESH: Developmental Disabilities / physiopathology, genetic structures, genotype-phenotype correlations, Developmental Disabilities, anophthalmia, Microphthalmia, MESH: Forkhead Transcription Factors / genetics, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Microphthalmos, Eye Abnormalities, MESH: Developmental Disabilities / genetics, Genetics (clinical), Genetics, Forkhead Transcription Factors, MESH: Aphakia / physiopathology, Phenotype, 3. Good health, cataract, Mutation (genetic algorithm), Female, MESH: Mutation, Genetic counseling, MESH: Eye Abnormalities / physiopathology, Biology, MESH: Aphakia / genetics, 03 medical and health sciences, Dysgenesis, MESH: Genetic Predisposition to Disease, medicine, Humans, Genetic Predisposition to Disease, Sclerocornea, Gene, MESH: Microphthalmos / physiopathology, Alleles, Anophthalmia, MESH: Humans, MESH: Alleles, aphakia, MESH: Microphthalmos / genetics, medicine.disease, eye diseases, MESH: Male, 030104 developmental biology, microphthalmia, MESH: Eye Abnormalities / genetics, Mutation, eye development, 030221 ophthalmology & optometry, anterior segment dysgenesis, FOXE3, sense organs, MESH: Female
Abstract: International audience; Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene-based therapies.
Published: 2018

18. Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants

Author: Guy Serre, Karl Skriner, Evan Reed, Johan Rönnelid, Per-Johan Jakobsson, Martin Cornillet, Monika Hansson, Lars Klareskog, Karin Lundberg, Rikard Holmdahl, Linda Mathsson-Alm, Lars Alfredsson, Uppsala University, Karolinska Institutet [Stockholm], Thermo Fisher Scientific Inc., Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Swedish research Council, The Swedish rheumatism Association, King Gustav V 80-year Foundation, and The Be the Cure EU consortium
Subjects: Male, 0301 basic medicine, rheumatoid arthritis, Arginine, autoantibodies, Peptide, Anti-Citrullinated Protein Antibodies, Arthritis, Rheumatoid, 0302 clinical medicine, immune system diseases, MESH: Arthritis, Rheumatoid / genetics, MESH: Smoking / immunology, Immunology and Allergy, Medicine, Multiplex, skin and connective tissue diseases, chemistry.chemical_classification, MESH: Aged, MESH: Middle Aged, biology, MESH: Anti-Citrullinated Protein, Smoking, MESH: Genetic Predisposition to Disease, MESH: Arginine / immunology, Middle Aged, MESH: Case-Control Studies, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Shared epitope, MESH: Young Adult, Rheumatoid arthritis, Female, Antibody, Adult, musculoskeletal diseases, Adolescent, Genotype, Immunology, Protein Array Analysis, MESH: Antibodies / blood, Sensitivity and Specificity, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Rheumatology, MESH: Arthritis, Rheumatoid / blood, Humans, Genetic Predisposition to Disease, Allele, Alleles, Aged, 030203 arthritis & rheumatology, MESH: Adolescent, MESH: Humans, business.industry, MESH: Alleles, Autoantibody, MESH: Adult, MESH: Smoking / adverse effects, medicine.disease, MESH: Male, MESH: Sensitivity and Specificity, 030104 developmental biology, chemistry, Case-Control Studies, biology.protein, MESH: Protein Array Analysis / methods, business, ant-ccp, MESH: Female, HLA-DRB1 Chains, MESH: Genotype HLA-DRB1 Chains / genetics
Abstract: IntroductionThe second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and smoking. Using a multiplex assay to detect multiple specific ACPA, we have investigated the fine specificity of individual ACPA responses and the biological impact of additional ACPA reactivity among anti-CCP2-negative patients.MethodsWe investigated 2825 patients with RA and 551 healthy controls with full data on anti-CCP2, HLA-DRB1* alleles and smoking history concerning reactivity against 16 citrullinated peptides and arginine control peptides with a multiplex array.ResultsThe prevalence of the 16 ACPA specificities ranged from 9% to 58%. When reactivity to arginine peptides was subtracted, the mean diagnostic sensitivity increased by 3.2% with maintained 98% specificity. Of the anti-CCP2-negative patients, 16% were found to be ACPA positive. All ACPA specificities associated with SE, and all but one with smoking. Correction for arginine reactivity also conveyed a stronger association with SE for 13/16 peptides. Importantly, when all ACPA specificities were analysed together, SE and smoking associated with RA in synergy among ACPA positive, but not among ACPA-negative subjects also in the anti-CCP2-negative subset.ConclusionsMultiplexing detects an enlarged group of ACPA-positive but anti-CCP2-negative patients with genetic and environmental attributes previously assigned to anti-CCP2-positive patients. The individual correction for arginine peptide reactivity confers both higher diagnostic sensitivity and stronger association to SE than gross ACPA measurement.
Published: 2018

19. Drug-Resistant Polymorphisms and Copy Numbers in Plasmodium falciparum, Mozambique, 2015

Author: Sonia Enosse, Quique Bassat, Eva De Carvalho, Marian Warsame, Pascal Ringwald, Crizolgo Salvador, Himanshu Gupta, Didier Menard, Eusebio Macete, Helder Bulo, Alfredo Mayor, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Universitat de Barcelona (UB), Barcelona Centre for International Health Research, Hospital Clinic (CRESIB), Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), Instituto Nacional de Saude [Maputo, Mozambique] (INS), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris], Institució Catalana de Recerca i Estudis Avançats (ICREA), Hospital Sant Joan de Déu [Barcelona], We thank the World Health Organization for providing the funds for this study, as well as the Instituto de Salud Carlos III (PI13/01478 cofunded by the Fondo Europeo de Desarrollo Regional, and CES10/021-I3SNS) to A.M. A.M. is also supported by the Departament d’Universitats i Recerca de la Generalitat de Catalunya, Agència de Gestió d'Ajuts Universitaris i de Recerca (2014SGR263). H.G. has a fellowship from the Overseas Postdoctoral Fellowship program by the Science and Engineering Research Board, Department of Science & Technology, Government of India (SB/OS/PDF-043/2015-16). The Centro de Investigaçao em Saude de Manhica receives major core funding from the Spanish Agency for International Cooperation. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya., Malaria Molecular Epidemiology (MMEU), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Epidemiology, medicine.medical_treatment, vector-borne infections, lcsh:Medicine, Drug resistance, plasmepsin2, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Artemisinin, Malaria, Falciparum, Mozambique, MESH: Plasmodium falciparum, K13, MESH: Malaria, Falciparum, Drug-Resistant Polymorphisms and Copy Numbers in Plasmodium falciparum, Mozambique, 2015, 3. Good health, Infectious Diseases, MESH: Drug Resistance, MESH: DNA Copy Number Variations, medicine.drug, Microbiology (medical), DNA Copy Number Variations, Sulfadoxine, MESH: Mozambique, 030106 microbiology, 030231 tropical medicine, Plasmodium falciparum, malaria, Dihydroartemisinin, Biology, parasites, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Antimalarials, Piperaquine, copy number, parasitic diseases, MESH: Polymorphism, Genetic, medicine, Humans, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, antimicrobial resistance, Alleles, Polymorphism, Genetic, MESH: Humans, Research, MESH: Alleles, lcsh:R, medicine.disease, biology.organism_classification, Moçambic, Virology, MESH: Antimalarials, Pyrimethamine, polymorphisms, Malaria
Abstract: One of the fundamental steps toward malaria control is the use of antimalarial drugs. The success of antimalarial treatment can be affected by the presence of drug-resistant populations of Plasmodium falciparum. To assess resistance, we used molecular methods to examine 351 P. falciparum isolates collected from 4 sentinel sites in Mozambique for K13, pfmdr1, pfcrt, and pfdhps polymorphisms and for plasmepsin2 (pfpm2) and pfmdr1 copy numbers. We found multiple copies of pfpm2 in 1.1% of isolates. All isolates carried K13 wild-type alleles (3D7-like), except 4 novel polymorphisms (Leu619Leu, Phe656Ile, Val666Val, Gly690Gly). Prevalence of isolates with pfcrt mutant (K76T) allele was low (2.3%). Prevalence of isolates with pfdhps mutant alleles (A437G and K540E) was >80%, indicating persistence of sulfadoxine/pyrimethamine resistance; however, markers of artemisinin were absent, and markers of piperaquine resistance were low. Piperaquine resistance isolates may spread in Mozambique as dihydroartemisinin/piperaquine drug pressure increases.
Published: 2018

20. Novel genes and insights in complete asthma remission: A genome-wide association study on clinical and complete asthma remission

Author: Don D. Sin, Anne Boudier, Nicole Probst-Hensch, F. N. Dijk, Ke Hao, Judith M. Vonk, Yohan Bossé, Maartje A.E. Nieuwenhuis, Valérie Siroux, Medea Imboden, Emmanuelle Bouzigon, M. van den Berge, Gerard H. Koppelman, Dirk Keidel, Alen Faiz, Dirkje S. Postma, Siroux, Valérie, University Medical Center Groningen [Groningen] (UMCG), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes (UGA), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), University of British Columbia (UBC), Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Merck Research Laboratories, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: 0301 basic medicine, Oncology, Male, Allergy, MESH: Asthma, CHILDHOOD, IL1RL1, Genome-wide association study, Spontaneous remission, MESH: Respiratory Function Tests, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, DISEASE, RESPONSIVENESS, MESH: Genotype, 0302 clinical medicine, MESH: Respiratory Mucosa, Immunology and Allergy, ADENOSINE 5'-MONOPHOSPHATE, MESH: Genetic Association Studies, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: Patient Outcome Assessment, Middle Aged, MESH: Gene Expression Regulation, 3. Good health, Respiratory Function Tests, Phenotype, Bronchial hyperresponsiveness, Female, Bronchial Hyperreactivity, MESH: Computational Biology, Adult, medicine.medical_specialty, Genotype, Immunology, Quantitative Trait Loci, SPUTUM EOSINOPHILS, PHENOTYPES, Single-nucleotide polymorphism, Respiratory Mucosa, MESH: Molecular Sequence Annotation, MESH: Phenotype, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Asthma, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Alleles, MESH: Bronchial Hyperreactivity, IL18R1, Computational Biology, Molecular Sequence Annotation, MESH: Adult, ADULTS, medicine.disease, MESH: Quantitative Trait Loci, MESH: Male, respiratory tract diseases, Patient Outcome Assessment, 030104 developmental biology, 030228 respiratory system, Gene Expression Regulation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Expression quantitative trait loci, MESH: Genome-Wide Association Study, RISK-FACTORS, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, FOLLOW-UP, business, MESH: Female, Genome-Wide Association Study
Abstract: © 2018 John Wiley & Sons Ltd Background: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. Objective: We performed a GWA study to develop insights in asthma remission. Methods: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. Results: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10−7) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. Conclusions and Clinical Relevance: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.
Published: 2018

21. Artemisinin-Resistant Plasmodium falciparum K13 Mutant Alleles, Thailand–Myanmar Border

Author: Tim J. Anderson, François Nosten, Shalini Nair, Valentine Duru, Benoit Witkowski, Didier Menard, Mikael Boullé, Marina McDew-White, Kanlaya Sriprawat, Aung Pyae Phyo, Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris], Laboratoire d'épidémiologie moléculaire, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Réseau International des Instituts Pasteur (RIIP), Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Texas Biomedical Research Institute, Territoires, économie, enjeux sociétaux (LARHRA TEES), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Pierre Mendès France - Grenoble 2 (UPMF)-École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Mahidol University [Bangkok], Texas Biomedical Research Institute [San Antonio, TX], University of Oxford [Oxford], This work was supported by grants from the Réseau International des Insituts Pasteur ACIP grant #A14-2012., We thank all the patients and their parents or guardians, and The Shoklo Malaria Research Unit is part of the Mahidol-Oxford University Research Unit, funded by the Wellcome Trust of Great Britain. Laboratory work at Texas Biomedical Research Institute was conducted in facilities constructed with support from Research Facilities Improvement Program grant C06 RR013556 and R017515 from the National Center for Research Resources of the National Institutes of Health and was funded by National Institute of Allergy and Infectious Diseases Grant R37AI048071.
Subjects: 0301 basic medicine, Letter, Epidemiology, genotype, Drug Resistance, lcsh:Medicine, Drug resistance, Myanmar, artemisinin resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genotype, Artemisinin, Malaria, Falciparum, parasite clearance half-life, ComputingMilieux_MISCELLANEOUS, MESH: Plasmodium falciparum, media_common, MESH: Malaria, Falciparum, MESH: Myanmar, Thailand, Artemisinins, 3. Good health, Infectious Diseases, MESH: Drug Resistance, medicine.drug, Microbiology (medical), Drug, MESH: Mutation, K13 mutant alleles, media_common.quotation_subject, 030106 microbiology, Plasmodium falciparum, Biology, parasites, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Antimalarials, Antibiotic resistance, parasitic diseases, MESH: Artemisinins, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, lcsh:RC109-216, antimicrobial resistance, Allele, Letters to the Editor, MESH: Thailand, Alleles, MESH: Humans, MESH: Alleles, lcsh:R, Artemisinin-Resistant Plasmodium falciparum K13 Mutant Alleles, Thailand–Myanmar Border, medicine.disease, biology.organism_classification, Virology, MESH: Antimalarials, Malaria, 030104 developmental biology, ring-stage survival assay, Mutation
Abstract: To the Editor: Artemisinin resistance (ART-R) in Plasmodium falciparum phenotypes may have evolved independently in various areas of the Greater Mekong Sub-region (1,2), prompting the World Health Organization to change its regional policy from containment to elimination (3). Risks associated with ART-R include compromised use of artemisinin combined therapy, partner drug resistance selection, total ART-R resistance, and geographic extension to other malaria-endemic regions (2,3). Characterization of ART-R in each setting and rapid update of listed phenotypes classified as in vitro resistant to this antimalarial drug are needed.
Published: 2016

22. 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

23. Sex-Based Genetic Association Study Identifies CELSR1 as a Possible Chronic Obstructive Pulmonary Disease Risk Locus among Women

Author: COPDGene, Josée Dupuis, Dawn L. DeMeo, George T. O'Connor, Peter J. Castaldi, Merry-Lynn McDonald, Edwin K. Silverman, Terri H. Beaty, Megan Hardin, Michael H. Cho, Kimberly Glass, Scott T. Weiss, Jody Senter-Sylvia, Kelan G. Tantisira, Jarrett D. Morrow, David A. Lomas, Hugues Aschard, Alvar Agusti, John E. Hokanson, James D. Crapo, Amund Gulsvik, Sunita Sharma, Per Bakke, Nan M. Laird, Craig P. Hersh, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Harvard School of Public Health
Subjects: Male, 0301 basic medicine, Vital capacity, Respiratory System, Clinical Biochemistry, growth and development, Genome-wide association study, MESH: Pulmonary Disease, Chronic Obstructive, Cardiorespiratory Medicine and Haematology, MESH: Cadherins, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Demography, genetics, Lung, Original Research, MESH: Aged, COPD, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Single Nucleotide, Middle Aged, Cadherins, MESH: Gene Expression Regulation, Obstructive lung disease, 3. Good health, Respiratory, Female, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Pulmonary and Respiratory Medicine, Chronic Obstructive, medicine.medical_specialty, Chronic Obstructive Pulmonary Disease, Genetic genealogy, Polymorphism, Single Nucleotide, MESH: Genetic Loci, chronic obstructive pulmonary disease, Pulmonary Disease, 03 medical and health sciences, Clinical Research, Internal medicine, Tobacco, Genetics, medicine, Humans, SNP, sex, Genetic Predisposition to Disease, MESH: Lung, Polymorphism, COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points Investigators, Molecular Biology, Alleles, Demography, Aged, Genetic association, genome-wide association study, MESH: Humans, Tobacco Smoke and Health, business.industry, Prevention, MESH: Alleles, Human Genome, Cell Biology, Heritability, medicine.disease, MESH: Male, respiratory tract diseases, 030104 developmental biology, Gene Expression Regulation, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, MESH: Genome-Wide Association Study, Physical therapy, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, MESH: Female
Abstract: International audience; Chronic obstructive pulmonary disease (COPD) is a complex disease with strong environmental and genetic influences and sexually dimorphic features. Although genetic risk factors for COPD have been identified, much of the heritability remains unexplained. Sex-based genetic association studies may uncover additional COPD genetic risk factors. We studied current and former smokers from COPD case-control cohorts (COPDGene non-Hispanic whites and African Americans, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points, and Genetics of Chronic Obstructive Lung Disease). COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity less than 0.70 and forced expiratory volume in 1 second percent predicted less than 80. Testing was performed across all cohorts and combined in a meta-analysis adjusted for age, pack-years, and genetic ancestry. We first performed genome-wide single-nucleotide polymorphism (SNP)-by-sex interaction testing on the outcome of COPD affection status. We performed sex-stratified association testing for SNPs with interaction P less than 10-6. We examined over 8 million SNPs in four populations, including 6,260 subjects with COPD (40.6% female) and 5,269 smoking control subjects (47.3% female). The SNP rs9615358 in the cadherin gene CELSR1 approached genome-wide significance for an interaction with sex (P = 1.24 × 10-7). In the sex-stratified meta-analysis, this SNP was associated with COPD among females (odds ratio, 1.37 [95% confidence interval, 1.25-1.49]; P = 3.32 × 10-7) but not males (odds ratio, 0.90 [95% confidence interval, 0.79-1.01]; P = 0.06). CELSR1 is involved in fetal lung development. In a human fetal lung tissue dataset, we observed greater CELSR1 expression in female compared with male samples. This SNP-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for COPD. Identifying sex-specific genetic risk factors may reveal new insights into sexually dimorphic features of COPD.
Published: 2017

24. Genetic and phenotypic analyses of sequential vpu alleles from HIV-infected IFN-treated patients

Author: José Alcamí, Nicoletta Casartelli, Bénédicte Vanwalscappel, Francisco Díez Fuertes, Sylvie Rato, Mayte Pérez-Olmeda, Fabrizio Mammano, Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Instituto de Salud Carlos III [Madrid] (ISC), Virus et Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) to F.M. and J.A., and by grants from the Spanish AIDS Research Network RD12/0017/0015 that is included in the Spanish I+D+I Plan and is co-financed by ISCIII-Subdirección General de Evaluación and European Funding for Regional Development (FEDER) and Spanish Ministry of Economy and Competitiveness FIS PI12/00506 to J.A. B.V. was a doctoral fellow of Sidaction, S.R. was a post-doctoral fellow of ANRS. F.D.F is supported by the Spanish Government's Sara Borrell postdoctoral Program CD12/00515., CASARTELLI, NICOLETTA, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, MESH: Human Immunodeficiency Virus Proteins, viruses, Human Immunodeficiency Virus Proteins, Cell, HIV Infections, medicine.disease_cause, MESH: HIV-1, Interferon, Viral Regulatory and Accessory Proteins, MESH: Antigens, CD, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Restriction factor, virus diseases, BST-2, MESH: HIV Infections, Phenotype, 3. Good health, medicine.anatomical_structure, CD4 Antigens, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Interferon-alpha, MESH: Viral Regulatory and Accessory Proteins, medicine.drug, Viral protein, Evolution, Viremia, Biology, GPI-Linked Proteins, MESH: Phenotype, MESH: CD4 Antigens, 03 medical and health sciences, Antigens, CD, Virology, Vpu, medicine, Humans, Viral shedding, Allele, Alleles, MESH: Humans, MESH: Alleles, Interferon-alpha, medicine.disease, 030104 developmental biology, Viral replication, Immunology, HIV-1, MESH: GPI-Linked Proteins
Abstract: International audience; Treatment of HIV-infected patients with IFN-α results in significant, but clinically insufficient, reductions of viremia. IFN induces the expression of several antiviral proteins including BST-2, which inhibits HIV by multiple mechanisms. The viral protein Vpu counteracts different effects of BST-2. We thus asked if Vpu proteins from IFN-treated patients displayed improved anti-BST-2 activities as compared to Vpu from baseline. Deep-sequencing analyses revealed that in five of seven patients treated by IFN-α for a concomitant HCV infection in the absence of antiretroviral drugs, the dominant Vpu sequences differed before and during treatment. In three patients, vpu alleles that emerged during treatment improved virus replication in the presence of IFN-α, and two of them conferred improved virus budding from cells expressing BST-2. Differences were observed for the ability to down-regulate CD4, while all Vpu variants potently down-modulated BST-2 from the cell surface. This report discloses relevant consequences of IFN-treatment on HIV properties.
Published: 2017

25. Vox Sanguinis International Forum on donor notification and counselling strategies for markers of transfusion-transmissible infections: summary

Author: E. Zhiburt, D. Teo, Pierre Gallian, Patricia E. Hewitt, W. C. Tsoi, Mark Bigham, Rachid Djoudi, Miquel Lozano, Senarath Banda Abeykoon Jayasekara, Salwa Hindawi, J. N. S. Leung, Margaret Fearon, D. Kessler, Geneviève Woimant, J. Chay, T. Huang, Harumichi Matsukura, Suchet Sachdev, P. J. M. van den Burg, A. G. Bokhorst, N. Shantseva, Celso Bianco, N. Moleli, Neelam Marwaha, Yoshihiko Tani, S. Oyonarte, R.R. Sharma, Kenji Tadokoro, Cheuk-Kwong Lee, Department of Hemotherapy and Hemostasis, University Clinical Hospital, Institute for Study of Earth, Oceans and Space, University of New Hampshire (UNH), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Emergence des Pathologies Virales (EPV), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, National Changhua University of Education (NCUE), Tohoku National Fisheries Research Institute, National Fisheries Research Institute, Department of Biological Environment, Akita University, Institute of Biomedical sciences, Academia Sinica, Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université de Bordeaux (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), and National Changhua University of Education
Subjects: Genotyping, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, MESH: Phenotype, 03 medical and health sciences, 0302 clinical medicine, Antigen, MESH: Genotyping Techniques, Genotype, MESH: Gene Frequency, Medicine, Multiplex, Allele, Allele frequency, High prevalence, MESH: Humans, MESH: Blood Group Antigens, business.industry, MESH: Alleles, MESH: Blood Donors, Allele frequencies, Hematology, General Medicine, MESH: Mali, MESH: Male, 3. Good health, Immunology, Africa, business, MESH: Female, 030215 immunology
Abstract: International audience; We determined the frequencies of clinically relevant blood group alleles in 300 blood donors from Mali. Multiplex test based on xMAP technology was used to investigate six blood group systems (RH, KEL, MNS, FY, JK, DO, HPA) and complementary analysis were conducted for MNS and RH systems. Polymorphisms that affect the specificity of molecular tests leading to discrepant genotype results are discussed. Antigen expressions were predicted showing that 50% of donors expressed at least one traditional low prevalence antigen, and 11.6% lacked the ability to express at least one high prevalence antigen compatible with Dob-, HPA1a-, S-s-U-, Jsb-, RH:-31 and/or RH:-34 phenotypes.
Published: 2016

26. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients

Author: Christine Petit, Eberhart Zrenner, Shzeena Dad, Martina Jarc-Vidmar, Maria Antonia Claveria, Alberto Auricchio, Ana Fakin, Marko Hawlina, Gaelle M. Lefèvre, Susanne Kohl, Anne Kurtenbach, Aziz El-Amraoui, Loreto Martorell Sampol, Jesus Rodriguez Jorge, Ditta Zobor, Saddek Mohand-Said, Crystel Bonnet, Ieva Sliesoraityte, Charles Marcaillou, Francesco Testa, Saba Battelino, Jaume Mora, Mélanie Letexier, José-Alain Sahel, Francesca Simonelli, Lisbeth Birk Møller, Sandra Chantot-Bastaraud, Jean-Pierre Hardelin, Isabelle Audo, Zied Riahi, Andrej Zupan, Luce Smagghe, Amrit Singh-Estivalet, Damjan Glavač, Souad Gherbi, Sandro Banfi, Sandrine Marlin, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), IntegraGen SA, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University of Tuebingen, Centre de référence des Surdités Génétiques [CHU Necker, Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II = Università degli studi di Napoli Federico II, Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Seconda Università degli Studi di Napoli = Second University of Naples, University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), University of Ljubljana, Hospital Sant Joan de Déu [Barcelona], Kennedy Center, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the European Union Seventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), ANR-15-RHUS-001 (LIGHT4DEAF), LHW-Stiftung, Fondation Raymonde & Guy Strittmatter, FAUN Stiftung, Conny Maeva Charitable Foundation, Fondation Orange, Fondation BNP Paribas, LABEX Lifesenses [ANR-10-LABX-65], 'the Foundation Fighting Blindness Paris Center Grant', and the Slovenian research agency (ARRS P3-0333)., We are grateful to the patients and their families for their participation in the study. DNA samples included in this study originated from the NeuroSensCol** DNA bank, part of the BioCollections network for research in neuroscience (PI: JA Sahel, co-PI: I Audo, in partnership with the CHNO des Quinze-Vingts, Inserm and the CNRS), and the Tuebingen RetDis biobank (PI: B Wissinger, co-PI S Kohl)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), Bonnet, Crystel, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID, Riahi, Zied, Chantot Bastaraud, Sandra, Smagghe, Luce, Letexier, Mélanie, Marcaillou, Charle, Lefèvre, Gaëlle M, Hardelin, Jean Pierre, El Amraoui, Aziz, Singh Estivalet, Amrit, Mohand Saïd, Saddek, Kohl, Susanne, Kurtenbach, Anne, Sliesoraityte, Ieva, Zobor, Ditta, Gherbi, Souad, Testa, Francesco, Simonelli, Francesca, Banfi, Sandro, Fakin, Ana, Glavač, Damjan, Jarc Vidmar, Martina, Zupan, Andrej, Battelino, Saba, Martorell Sampol, Loreto, Claveria, Maria Antonia, Catala Mora, Jaume, Dad, Shzeena, Møller, Lisbeth B, Rodriguez Jorge, Jesu, Hawlina, Marko, Auricchio, Alberto, Sahel, José Alain, Marlin, Sandrine, Zrenner, Eberhart, Audo, Isabelle, Petit, Christine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de référence des Surdités Génétiques, University of Naples Federico II, Seconda Università degli studi di Napoli, and Chaire Génétique et physiologie cellulaire
Subjects: 0301 basic medicine, MESH: Extracellular Matrix Proteins, MESH: Sequence Analysis, DNA, Usher syndrome, [SDV]Life Sciences [q-bio], Bioinformatics, 0302 clinical medicine, Exome, Exome sequencing, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Extracellular Matrix Proteins, MESH: Exome, medicine.diagnostic_test, MESH: Genetic Testing, 3. Good health, Europe, [SDV] Life Sciences [q-bio], Medical genetics, MESH: Genes, Modifier, Usher Syndromes, medicine.medical_specialty, MESH: Mutation, Genetic counseling, Biology, Sensitivity and Specificity, Article, 03 medical and health sciences, Molecular genetics, medicine, otorhinolaryngologic diseases, Humans, Genetic Testing, MESH: Usher Syndromes, Alleles, Genetic testing, Genes, Modifier, MESH: Humans, Genetic heterogeneity, MESH: Alleles, Sequence Analysis, DNA, medicine.disease, MESH: Sensitivity and Specificity, MESH: Comparative Genomic Hybridization, 030104 developmental biology, Mutation, 030221 ophthalmology & optometry, MESH: Europe
Abstract: International audience; Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
Published: 2016

27. Presence of calreticulin mutations in JAK2-negative polycythemia vera

Author: Julien Broséus, Serge Carillo, François Girodon, Sylvie Hermouet, Ji-Hye Park, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de ressources biologiques Ferdinand Cabanne [Dijon] (CRB Ferdinand Cabanne), and Herrada, Anthony
Subjects: Male, Erythrocytes, MESH: Thrombocytosis, medicine.disease_cause, MESH: Polycythemia Vera, Biochemistry, MESH: Janus Kinase 2, MESH: Genotype, Hemoglobins, MESH: Aged, 80 and over, Polycythemia vera, hemic and lymphatic diseases, Polycythemia Vera, MESH: Heterozygote, Aged, 80 and over, Thrombocytosis, MESH: Aged, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Janus kinase 2, biology, MESH: Erythrocytes, Exons, Hematology, Leukemia, MESH: Hemoglobins, MESH: Primary Myelofibrosis, Thrombocythemia, Essential, Heterozygote, MESH: Mutation, Genotype, MESH: Calreticulin, Immunology, Context (language use), medicine, Humans, Myelofibrosis, Alleles, Aged, MESH: Humans, Essential thrombocythemia, business.industry, MESH: Alleles, Cell Biology, Janus Kinase 2, medicine.disease, MESH: Male, Primary Myelofibrosis, MESH: Gene Deletion, biology.protein, Cancer research, MESH: Thrombocythemia, Essential, Calreticulin, MESH: Exons, business, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Calreticulin (CALR) mutations have recently been reported in JAK2- and MPL-negative Myeloproliferative Neoplasms (MPN), particularly essential thrombocythemia (ET) and primary myelofibrosis (PMF).The clinical course of sporadic CALR-mutated patients seems to be more indolent than that of JAK2-mutated patients. In contrast, no CALR mutation has been found in the 647 published cases of Polycythemia Vera (PV) patients tested. Consequently, CALR mutations were considered exclusive to JAK2 and MPL mutations. Since 98% of PV patients harbor a JAK2 mutation (mostly the V617F mutation in exon 14 and more rarely, in exon 12), the absence of CALR mutations in PV seemed logical. Here, we describe two JAK2V617F-negative PV patients who presented with a CALR mutation at the time of diagnosis. Patient # 1 had hemoglobin at 168 g/L, hematocrit at 51.3%, and increased red cell mass (RCM) at 128% associated with a normal erythropoietin level. The bone marrow biopsy showed hypercellularity for age, panmyelosis associated with normal megakaryocytes and rare isolated abnormal enlarged forms. Using reticulin stain, no myelofibrosis was noted. Patient # 2 had hemoglobin at 194 g/L, hematocrit at 53% and low erythropoietin level without any dehydration. Both had moderately elevated platelet counts (658 and 575 x109/L respectively) with normal leukocyte counts. They were negative for BCR-ABL. No mutation was found in JAK2 exons 12, 13 and 14 by HRM and allele-specific real-time PCR or in MPL exon 10. Using HRM analysis, CALR mutations were suspected in both patients and confirmed using Sanger sequencing and product sizing analyses: CALR mutations were in both patients type 1 deletions (52-bp deletion; c.1092_1143del). To complete genomic tests made on peripheral blood granulocytes, we performed colony assays in methylcellulose and in collagen, picked single BFU-E colonies grown after 14 days in the presence of erythropoietin, and genotyped each colony individually for CALR. Of the 27 colonies genotyped, 6 had no PCR amplification and 21 harboured the same CALR mutation observed in peripheral blood granulocytes, i.e 52-bp deletion; c.1092_1143del. BFU-E were found heterozygous for CALR, with a mean allele burden of 49%. To our knowledge, these patients are the first cases of CALR-mutated PV to be reported. However, since a biclonalJAK2V617F and CALR MPN case recently reported, we cannot rule out the possibility of a biclonal disease involving a yet unknown mutation associated with a CALR mutation. On the other hand, the presence of a CALR mutation both in peripheral granulocytes and in BFU-E suggests that the CALR mutation plays a role in the polycythemia phenotype. Our observations highlight the fact that in the absence of JAK2 mutation, CALR mutations can also be associated with PV. In conclusion, our data indicate that testing JAK2-negative PV patients for CALR mutations may be useful. Disclosures No relevant conflicts of interest to declare.
Published: 2014

28. Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients

Author: Agustin Barnadas, Harry Ostrer, Søren M. Bentzen, David Azria, Rebecca Elliott, C.A. Koch, John Yarnold, Petra Seibold, M. Molla, Christian Nicolaj Andreassen, Laura Fachal, Ana Vega, David P. Dearnaley, Emma Hall, Barry S. Rosenstein, Sarah L. Kerns, Michael Blackshaw, Piet Ost, Matthew Parliament, Marie Overgaard, Jamie A. Cesaretti, Catharine M L West, Teresa Ramón y Cajal, Michael Sia, Charlotte E. Coles, Orland Diez, Dirk De Ruysscher, Matthew R. Sydes, Jenny Chang-Claude, Antonio Gómez-Caamaño, Jan Alsner, Christopher J. Talbot, Maria J. Fuentes-Raspall, Odilia Popanda, Gillian C. Barnett, Jens Overgaard, Neil G. Burnet, Hubert Thierens, Leila Dorling, Sara Gutiérrez-Enríquez, R. Paul Symonds, Danny Vesprini, Alison M. Dunning, Kim De Ruyck, Radiotherapie, RS: FHML non-thematic output, RS: GROW - School for Oncology and Reproduction, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Oncology, Male, Pathology, MESH: Radiotherapy, medicine.medical_treatment, Ataxia Telangiectasia Mutated Proteins, Radiation Tolerance, p.Asp1853Asn, +A%22">c.5557G > A, MESH: Genotype, Prostate cancer, 0302 clinical medicine, A%22">c.5557G>A, MESH: Risk Factors, Risk Factors, Odds Ratio, Medicine, MESH: Ataxia Telangiectasia Mutated Proteins, MESH: Heterozygote, MESH: Radiation Tolerance, MESH: Middle Aged, Manchester Cancer Research Centre, Research Support, Non-U.S. Gov't, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Hematology, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Toxicity, Female, Normal tissue toxicity, medicine.medical_specialty, Heterozygote, Genotype, Radiogenomics, MESH: Radiation Injuries, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Polymorphism, Single Nucleotide, Article, Radiosensitivity, 03 medical and health sciences, Breast cancer, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, Humans, Radiology, Nuclear Medicine and imaging, Genetic Predisposition to Disease, Radiation Injuries, Alleles, Ataxia telangiectasia mutated, MESH: Humans, Radiotherapy, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, MESH: Alleles, Prostatic Neoplasms, Odds ratio, medicine.disease, Acute toxicity, MESH: Odds Ratio, MESH: Male, Radiation therapy, 030104 developmental biology, MESH: Prostatic Neoplasms, business, MESH: Female, MESH: Breast Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Meta-Analysis
Abstract: Purpose: Several small studies have indicated that the ATM rsl 801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. Materials and methods: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. Results: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. Conclusion: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Published: 2016

29. X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations

Author: Hicham Charoute, Jalel Chemli, Nabila Attal, Leila Jeddane, Yu-Lung Lau, Sara El Atiqi, Rachid Saile, Ahmed Aziz Bousfiha, Chawki Kaddache, Imen Ben-Mustapha, Fethi Mellouli, Naima El Hafidi, Mohamed Bejaoui, Hanane Salih Alj, Nabila Touri, Zahra Aadam, Leila Smati, Rachida Boukari, Mustapha Hida, Fatouma Doudou, Mohamed-Cherif Abbadi, Tahar Gargah, I. Brini, Fatima Ailal, J. Najib, Amina Bakhchane, Mohamed-Ridha Barbouche, Meriem Ben-Ali, Nadia Kechout, Koon-Wing Chan, Fethi Zidi, Abdelhamid Barakat, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), Université Hassan II [Casablanca] (UH2MC), Institut Pasteur d'Algérie, Department of Paediatrics and Adolescent Medicine [HKU], The University of Hong Kong (HKU), Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Department of Pediatrics [Tozeur], Regional Hospital of Tozeur, Faculté des Sciences Aïn Chock [Casablanca] (FSAC), Centre Hospitalo-Universitaire de Blida (CHU Blida), Faculté de médecine d'Alger, Université d'Alger 1 (Benyoucef Benkhedda), Hôpital Universitaire Sahloul (CHU Sahloul), Hôpital Charles Nicolle [Tunis], Hôpital d'enfants de Tunis, Avicenne University Hospital [Rabat], Centre Hospitalier Universitaire Hassan II (CHU HII), Centre National de Greffe de la Moëlle osseuse Tunis (CNGMO), and This work was supported by ACIP: A-07-2011 (Actions Concertées Inter Pasteuriennes) from the International Network of Pasteur Institutes (RIIP).
Subjects: Male, 0301 basic medicine, MESH: Sequence Analysis, DNA, Gene Expression, MESH: Genetic Diseases, X-Linked/immunology, Gene mutation, medicine.disease_cause, MESH: Protein-Tyrosine Kinases/immunology, 0302 clinical medicine, Gene Frequency, Agammaglobulinemia, hemic and lymphatic diseases, MESH: Child, Agammaglobulinaemia Tyrosine Kinase, Immunology and Allergy, Medicine, Missense mutation, Age of Onset, Child, MESH: Genetic Diseases, X-Linked/complications, novel mutations, MESH: Genetic Association Studies, MESH: Heterozygote, Sanger sequencing, Genetics, B-Lymphocytes, Mutation, biology, MESH: Opportunistic Infections/diagnosis, MESH: Agammaglobulinemia/diagnosis, Genetic Diseases, X-Linked, Protein-Tyrosine Kinases, MESH: Agammaglobulinaemia Tyrosine Kinase, MESH: Infant, 3. Good health, Morocco, BTK, Child, Preschool, MESH: Agammaglobulinemia/immunology, symbols, MESH: Opportunistic Infections/immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Genetic Counseling, MESH: Tunisia, MESH: Algeria, Adult, Heterozygote, XLA, Tunisia, north african population, MESH: Age of Onset, Immunology, Nonsense mutation, MESH: B-Lymphocytes/pathology, MESH: Opportunistic Infections/genetics, Genetic Counseling, Opportunistic Infections, MESH: B-Lymphocytes/immunology, Frameshift mutation, 03 medical and health sciences, symbols.namesake, MESH: Opportunistic Infections/complications, MESH: Genetic Diseases, X-Linked/genetics, Humans, Bruton's tyrosine kinase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Gene Frequency, Alleles, Genetic Association Studies, MESH: Humans, business.industry, MESH: Alleles, MESH: Child, Preschool, Infant, MESH: Adult, Sequence Analysis, DNA, MESH: Agammaglobulinemia/complications, medicine.disease, MESH: Gene Expression, MESH: Male, 030104 developmental biology, MESH: Protein-Tyrosine Kinases/genetics, MESH: Genetic Diseases, X-Linked/diagnosis, Algeria, MESH: Morocco, Primary immunodeficiency, biology.protein, MESH: Mutation, MESH: Agammaglobulinemia/genetics, business, 030215 immunology
Abstract: International audience; X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2 % peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5 % vs 85 %). No strong evidence for genotype-phenotype correlation was observed. This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.
Published: 2016

30. Genetic micro-heterogeneity of Leishmania major in emerging foci of zoonotic cutaneous leishmaniasis in Tunisia

Author: Carola Schweynoch, Hanène Attia, Gabriele Schönian, Rabiaa M. Sghaier, Ghada Mkannez, Sadok Chlif, Tesfaye Gelanew, Dhafer Laouini, Koussay Dellagi, Fatma Z. Guerfali, Aymen Bali, Nabil Belhaj-Hamida, Université de Tunis El Manar (UTM), Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Laboratoire d'Epidémiologie Médicale, Institut Pasteur de Tunis, This work was supported by an NIH/NIAID/DMID Grant Number 5P50AI074178 and the Tunisian Ministry of Higher Education and Research (LR11 IPT02) for KD and DL., and We are grateful to Prof. A. Ben Salah and Mr. A. Zaatour for kindly providing us with L. major isolates from the field. We thank Ms. R. Yazidi and Ms. S. Chaâbane for their valuable technical help. We are thankful to Dr. K. Ben-Aissa for her English and grammar corrections and to Dr. J Bettaieb for her advices on statistical analyses.
Subjects: 0301 basic medicine, MESH: Leishmaniasis, Cutaneous/transmission, MESH: Leishmania major/genetics, Endemic Diseases, MESH: Tunisia/epidemiology, MESH: Genome, Protozoan, Zoonoses, Leishmania major, MESH: Animals, Phylogeny, MESH: Phylogeny, Genetics, Phylogenetic tree, MESH: Genetic Heterogeneity, 3. Good health, Emerging focus, MESH: Endemic Diseases, MESH: Leishmania major/classification, Infectious Diseases, MESH: Multilocus Sequence Typing, Parasitic disease, Genetic structure, Microsatellite, MESH: Zoonoses, Microbiology (medical), Tunisia, MESH: Psychodidae/parasitology, MESH: Leishmaniasis, Cutaneous/epidemiology, Leishmaniasis, Cutaneous, Locus (genetics), Biology, MESH: DNA, Protozoan/genetics, Microbiology, MESH: Genetic Loci, 03 medical and health sciences, Genetic Heterogeneity, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Typing, Allele, Molecular Biology, MESH: Life Cycle Stages/genetics, Ecology, Evolution, Behavior and Systematics, Alleles, Multi-locus microsatellite typing, MESH: Leishmaniasis, Cutaneous/parasitology, Life Cycle Stages, MESH: Humans, MESH: Alleles, DNA, Protozoan, biology.organism_classification, medicine.disease, MESH: Leishmania major/isolation & purification, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Old focus, MESH: Microsatellite Repeats, Heterogeneity, Psychodidae, MESH: Leishmania major/growth & development, Genome, Protozoan, Zoonotic cutaneous leishmaniasis, Microsatellite Repeats, Multilocus Sequence Typing
Abstract: International audience; Tunisia is endemic for zoonotic cutaneous leishmaniasis (ZCL), a parasitic disease caused by Leishmania (L.) major. ZCL displays a wide clinical polymorphism, with severe forms present more frequently in emerging foci where naive populations are dominant. In this study, we applied the multi-locus microsatellite typing (MLMT) using ten highly informative and discriminative markers to investigate the genetic structure of 35 Tunisian Leishmania (L.) major isolates collected from patients living in five different foci of Central Tunisia (two old and three emerging foci). Phylogenetic reconstructions based on genetic distances showed that nine of the ten tested loci were homogeneous in all isolates with homozygous alleles, whereas one locus (71AT) had a 58/64-bp bi-allelic profile with an allele linked to emerging foci. Promastigote-stage parasites with the 58-bp allele tend to be more resistant to in vitro complement lysis. These results, which stress the geographical dependence of the genetic micro-heterogeneity, may improve our understanding of the ZCL epidemiology and clinical outcome.
Published: 2016

31. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

Author: Iman K. Al-Azwani, Eman K. Al-Dous, Eliane Mery, Alejandra Martinez, Joel A. Malek, Hanif Khalak, Yasmin A. Mohamoud, Denis Querleu, Cameron McLurcan, Laurence Puydenus, Pascal Pujol, Najeeb Halabi, Gwenael Ferron, Halema Alfarsi, Arash Rafii, Weill Medical College of Cornell University [New York], Institut Claudius Regaud, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Weill Cornell Medical College in Qatar (WCMC-Q), Weill Cornell Medicine [Qatar], University of Birmingham [Birmingham], Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, and Herrada, Anthony
Subjects: MESH: Neoplasm Proteins, 0301 basic medicine, Cancer Research, MESH: Mutation, lcsh:QH426-470, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Biology, Germline, Targeted therapy, Metastasis, Transcriptome, 03 medical and health sciences, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Allele, MESH: High-Throughput Nucleotide Sequencing, Molecular Biology, Gene, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, MESH: Gene Regulatory Networks, MESH: Humans, MESH: Alleles, MESH: Transcriptome, MESH: Allelic Imbalance, Cancer, MESH: Gene Expression Regulation, Neoplastic, medicine.disease, 3. Good health, lcsh:Genetics, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, MESH: Ovarian Neoplasms, MESH: Germ Cells, 030104 developmental biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Female, Research Article
Abstract: Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies., Author Summary Identifying genes that contribute to cancer biology is complicated partly because cancers can have dozens of somatic mutations and thousands of germline variants. Somatic mutations are gene variants that arise after conception in an organism while germline variants are gene variants present at conception in an organism. Most methods to identify cancer drivers have focused on determining somatic mutations. In this study we attempt to identify, from a tumor sample, important germline and somatic variants by determining if a variant is expressed (made into RNA) more than expected from the amount of the variant in the genome. The preferred expression of a variant could benefit cancer cells. When applying our analysis to ovarian cancer samples we found that despite the apparent heterogeneity, different patients frequently share the same genes with preferentially expressed variants. These genes in many cases are known to affect cancer processes such as DNA repair, cell adhesion and cell signaling and are targetable with known drugs. We therefore conclude that our analysis can identify germline and somatic gene variants that contribute to cancer biology and can potentially guide individualized therapies.
Published: 2016

32. Estrogen receptor alpha gene variants and major depressive episodes

Author: Marie-Laure Ancelin, Pierre-Yves Scarabin, Isabelle Carrière, Karen Ritchie, Olivier Rouaud, Joanne Ryan, Karine Pérès, Jacqueline Scali, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Fondation FondaMental [Créteil], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie, Université Montpellier 1 (UM1)-Hôpital Guy de Chauliac-Centre Mémoire Ressources Recherche Languedoc - Roussillon, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Faculty of Medicine, Imperial College London, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Villebrun, Dominique, and Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Estrogen receptor, MESH: Logistic Models, Logistic regression, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Genetic Variation, elderly women, MESH: Estrogen Receptor alpha, Depression (differential diagnoses), [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Aged, Aged, 80 and over, estrogen receptor polymorphisms, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Menopause, Psychiatry and Mental health, Clinical Psychology, recurrent depressive episodes, Major depressive disorder, Female, medicine.medical_specialty, medicine.drug_class, MESH: Depressive Disorder, Major, 03 medical and health sciences, Internal medicine, MESH: Polymorphism, Genetic, medicine, Humans, Allele, Alleles, Aged, Depressive Disorder, Major, MESH: Humans, Polymorphism, Genetic, major depressive disorder, business.industry, MESH: Alleles, Estrogen Receptor alpha, Genetic Variation, medicine.disease, 030227 psychiatry, Logistic Models, Endocrinology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Estrogen, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, Estrogen receptor alpha, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Despite evidence of estrogen's mood-enhancing effects, the association between estrogen receptor (ER) gene variants and lifetime major depression has been insufficiently studied. METHODS: 3987 community-dwelling women aged 65years and over were recruited in France as part of the Three City Study. Current and past major depressive disorders (MDD) were diagnosed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. The association between two common estrogen receptor alpha (ESR1) polymorphisms with lifetime MDD was examined using adjusted logistic regression models, taking into account the age at first depressive episode and the recurrence of depression. RESULTS: Women homozygous for the variant G allele of ESR1 rs9340799 had a 1.6-fold increased risk of MDD across their lifetime compared with women who were homozygous for the A allele (p=0.009). There was a similar non-significant trend for the C allele of rs2234693 being associated with an increased risk (p=0.09). Polytomous regression analysis further indicated that the GG genotype of rs9340799 was specifically associated with an increased risk of recurrent depressive episodes, regardless of the age at first onset of depression relative to the menopause. LIMITATIONS: The duration and severity of depressive episodes was not considered in the analysis. CONCLUSIONS: This is the first study to examine the association between ESR1 gene variants and lifetime MDD. Our findings indicate a significant association between common variants and the risk of recurrent depressive episodes. This suggests that certain depressed women could be most responsive to hormone-based treatment.
Published: 2012

33. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum

Author: Pierre Sarda, Guilhem Solé, Fabienne Giuliano, Cyril Goizet, Marie-Ange Delrue, Eva-Lena Stattin, Patricia Fergelot, Nada Houcinat, Hubert Journel, Jacqueline Vigneron, Elisabeth Sarrazin, Benoit Arveiler, S. Deves, Laurence Faivre, Albert David, Clarisse Baumann, Martine Le Merrer, Caroline Abadie, Caroline Rooryck, Elodie Guerineau, Sophie Naudion, Marie-Laure Vuillaume, Nicolas Chassaing, Julie Bouron, Sébastien Moutton, Isabelle Coupry, David Geneviève, Marie-Pierre Cordier, Julie Deforges, Christine Francannet, Didier Lacombe, Danielle Leclair, André Mégarbané, Christophe Hubert, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Arabian Gulf University, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de médecine physique et réadaptation [CHU Raymond-Poincaré], Hôpital Raymond Poincaré [AP-HP], AP-HP Hôpital universitaire Robert-Debré [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Bretagne Atlantique [Vannes], Service de génétique médicale [Clermont-Ferrand], CHU Clermont-Ferrand, and AP-HP Hôpital Raymond Poincaré [Garches]
Subjects: 0301 basic medicine, Proband, Male, MESH: Sequence Analysis, DNA, 030105 genetics & heredity, Bioinformatics, medicine.disease_cause, Craniofacial Abnormalities, FLNA, Missense mutation, Genetics (clinical), Genetics, MESH: Osteochondrodysplasias / genetics, Mutation, MESH: Hand Deformities, Congenital / genetics, Exons, MESH: Amino Acid Substitution, Pedigree, Phenotype, MESH: Facies, Statistical genetics, Medical genetics, Female, MESH: Osteochondrodysplasias / diagnosis, MESH: Genetic Association Studies, Hand Deformities, Congenital, medicine.medical_specialty, MESH: Pedigree, MESH: Phenotype, Filamins, Biology, Osteochondrodysplasias, MESH: Craniofacial Abnormalities / diagnosis, 03 medical and health sciences, medicine, Humans, MESH: Filamins / genetics, Alleles, Genetic Association Studies, MESH: Hand Deformities, Congenital / diagnosis, MESH: Humans, MESH: Alleles, Facies, Sequence Analysis, DNA, medicine.disease, MESH: Craniofacial Abnormalities / genetics, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, Dysplasia, MESH: Mutation, MESH: Exons, MESH: Female
Abstract: International audience; Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.
Published: 2015

34. Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes

Author: Vicente C. Quintanilla, Cecilia R Giulivi, Donna F. Kusewitt, Jimi L. Brandon, Fernando Benavides, Jean Jaubert, Kirstin F. Barnhart, Irma B. Gimenez-Conti, Nancy W. Otto, Catherine Ross-Inta, John DiGiovanni, Claudio J. Conti, Carlos J. Perez, Jean-Louis Guénet, Isabelle Aubin, The University of Texas M.D. Anderson Cancer Center [Houston], Graduate School of Biomedical Sciences [Houston], The University of Texas Health Science Center at Houston (UTHealth)-The University of Texas M.D. Anderson Cancer Center [Houston], Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris] (IP), Michale E. Keeling Center for Comparative Medicine and Research [Bastrop, Texas], School of Veterinary Medicine [Univ California Davis] (VetMed - UC Davis), University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Génétique fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Supported by National Institutes of Health grant CA90922 (C.J.C.), Department of Health and Human Services/National Cancer Institute grants P30 CA016672 (F.B. and D.F. K.) and P30 ES007784 (I.G.C.), and funding from Autism Speaks (C.G.)., We thank the Research Animal Support Facility-Smithville for their assistance with the maintenance of the mouse strains. We also thank Kevin Lin for statistical analyses, the Histology and Tissue Processing Facility Core for the IHC, and the Molecular Biology Facility Core for DNA sequencing., We are grateful to Brenda Webb (Michale E. Keeling Center) for her excellent technical skills with blood sampling. We thank Qin Sun (BCM Medical Genetics Laboratories) for the plasma amino acid analysis and ASS liver activity assays., Institut Pasteur [Paris], School of Veterinary Medicine [UC Davis], University of California-University of California, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Disease Models, Animal, Cerebellum, MESH: Mice, Mutant Strains, Developmental Disabilities, Argininosuccinate synthase, MESH: Sodium Benzoate / pharmacology, MESH: Mice, Knockout, Immunoenzyme Techniques, Mice, 0302 clinical medicine, Cell Movement, Sodium Benzoate, Hyperammonemia, MESH: Animals, MESH: Syndrome, MESH: Cell Movement, Growth Disorders, Mice, Knockout, Citrullinemia, 0303 health sciences, biology, MESH: Developmental Disabilities / etiology, Syndrome, MESH: Arginine / pharmacology, MESH: Mutation, Missense / genetics, MESH: Hyperammonemia / etiology, Phenotype, MESH: Citrullinemia / etiology, 3. Good health, medicine.anatomical_structure, Urea cycle, MESH: Argininosuccinate Synthase / physiology, Female, medicine.symptom, medicine.medical_specialty, Ataxia, Urea cycle disorder, Blotting, Western, Mutation, Missense, Argininosuccinate Synthase, MESH: Developmental Disabilities / drug therapy, Arginine, Nitric Oxide, MESH: Hyperammonemia / drug therapy, MESH: Phenotype, Pathology and Forensic Medicine, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Growth Disorders / etiology, medicine, Animals, Humans, MESH: Blotting, Western, MESH: Growth Disorders / drug therapy, Allele, MESH: Immunoenzyme Techniques, MESH: Mice, Alleles, 030304 developmental biology, MESH: Humans, MESH: Alleles, medicine.disease, MESH: Cerebellum / abnormalities, Mice, Mutant Strains, MESH: Male, Mice, Inbred C57BL, Disease Models, Animal, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Endocrinology, biology.protein, MESH: Nitric Oxide / metabolism, MESH: Female, MESH: Citrullinemia / drug therapy, 030217 neurology & neurosurgery, Regular Articles
Abstract: International audience; Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.
Published: 2010

35. Multiple RNA Surveillance Mechanisms Cooperate to Reduce the Amount of Nonfunctional Igκ Transcripts

Author: Guillaume Chemin, Michel Cogné, Aurélien Tinguely, Fabien Lechouane, Sophie Duchez, Laurent Delpy, Christophe Sirac, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), and Université de Limoges (UNILIM)
Subjects: Transcription, Genetic, MESH: Gene Rearrangement, B-Lymphocyte, Light Chain, MESH: Codon, Terminator, MESH: Down-Regulation, Mice, 0302 clinical medicine, Transcription (biology), Gene Rearrangement, B-Lymphocyte, Light Chain, Immunology and Allergy, MESH: Animals, MESH: Codon, Nonsense, Frameshift Mutation, Recombination, Genetic, Genetics, MESH: Plasma Cells, 0303 health sciences, Stem Cells, MESH: Frameshift Mutation, Cell Differentiation, medicine.anatomical_structure, Codon, Nonsense, RNA splicing, Codon, Terminator, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Recombination, Genetic, MESH: Cell Differentiation, MESH: Cell Line, Tumor, RNA Splicing, Plasma Cells, Immunology, MESH: Immunoglobulin kappa-Chains, Down-Regulation, MESH: Stem Cells, Biology, Frameshift mutation, Immunoglobulin kappa-Chains, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, RNA, Messenger, MESH: Mice, Gene, Alleles, B cell, MESH: RNA, Messenger, 030304 developmental biology, Messenger RNA, MESH: Alleles, MESH: Transcription, Genetic, RNA surveillance, Open reading frame, MESH: RNA Splicing, 030215 immunology
Abstract: Random V(D)J junctions ensure that the diversity of the Ig primary repertoire is adapted to the vast heterogeneity of Ags. In two-thirds of cases, recombination between variable segments induces a frameshift in the open reading frame and generates a premature termination codon. In B cells harboring biallelic V(D)J rearrangement of Ig genes, transcription is known to occur on both the functional and nonfunctional alleles, generating considerable amounts of primary transcripts with out-of-frame V regions. In this study, we analyzed in cell lines and primary B cells the RNA surveillance of nonfunctional Igκ transcripts arising from nonproductive rearrangement. We demonstrated that splicing inhibition, nonsense-mediated decay and nonsense-altered splicing each have an individual partial effect that together associate into an efficient surveillance machinery, downregulating nonfunctional Igκ mRNA. Moreover, we provide evidence that the RNA surveillance efficiency increases throughout B cell development. Whereas splicing inhibition remains constant in most cell lines, differences in nonsense-mediated decay and nonsense-altered splicing are responsible for the higher RNA surveillance observed in plasma cells. Altogether, these data show that nonfunctionally rearranged alleles are subjected to active transcription but that multiple RNA surveillance mechanisms eradicate up to 90% of out-of-frame Igκ mRNA.
Published: 2010

36. αIIbβ3 integrin: new allelic variants in Glanzmann thrombasthenia, effects onITGA2BandITGB3mRNA splicing, expression, and structure-function

Author: Jenny Goudemand, Nathalie Hézard, Alexandre G. de Brevern, Vincent Jallu, Simon Panzer, Marie-Francoise Torchet, Cécile Kaplan, Mathilde Dusseaux, Laboratoire d'immunologie plaquettaire, Institut National de la Transfusion Sanguine [Paris] (INTS), Department of Blood Group Serology and Transfusion Medicine, Medizinische Universität Wien = Medical University of Vienna, Centre des Hémophiles, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Reims Champagne-Ardenne (URCA), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The work done by M. Dusseaux was supported by a grant from Novo Nordisk
Subjects: MESH: Integrin beta3, Fibrinogen receptor, DNA Mutational Analysis, Mutant, Integrin alpha2, MESH: Base Sequence, 030204 cardiovascular system & hematology, medicine.disease_cause, MESH: Receptors, Fibrinogen, Exon, MESH: Structure-Activity Relationship, 0302 clinical medicine, Chlorocebus aethiops, Missense mutation, MESH: Animals, MESH: DNA Mutational Analysis, ITGB3, Genetics (clinical), Genetics, 0303 health sciences, Mutation, alphaIIbbeta3, MESH: Alternative Splicing, Integrin beta3, MESH: Gene Expression Regulation, MESH: Thrombasthenia, MESH: COS Cells, ITGA2B, COS Cells, RNA splicing, Thrombasthenia, Molecular Sequence Data, MESH: Integrin alpha2, Biology, Structure-Activity Relationship, 03 medical and health sciences, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Alleles, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, MESH: Alleles, Alternative splicing, MESH: Cercopithecus aethiops, Molecular biology, Alternative Splicing, Receptors, Fibrinogen, Gene Expression Regulation, Protein structure modeling, Glanzmann
Abstract: International audience; Glanzmann thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation due to defects in integrin alphaIIbbeta3 (ITGA2B, ITGB3), a fibrinogen receptor. Mutations from 24 GT patients and two carriers of various origins, Caucasian, North-African and Asian were characterized. Promoter and exon sequences of alphaIIb and beta3 genes were amplified and directly sequenced. Among 29 identified mutations, 17 new allelic variants resulting from nonsense, missense and deletion/insertion mutations were described. RNA alterations were evaluated by using Web servers. The alphaIIb p.S926L, p.V903F, and beta3 p.C38Y, p.M118R, p.G221D substitutions prevented complex expression at the surface of COS-7 cells by altering the alphaIIb or the beta3 subunit structure. As shown by free energy analyses applied on the resolved structure of alphaIIbbeta3 and structural modeling of the mutant, the p.K253M substitution of beta3 helped to define a key role of the K253 in the interaction of the alphaIIb beta-propeller and the beta3 beta-I domains. finally, the alphaIIb p.Q595H substitution allowed cell surface expression of the complex but its corresponding c.2800G>T mutation is predicted to alter normal RNA splicing. In conclusion, our study yielded the discovery of 17 new GT allelic variants, revealed the key role of K253 of alphaIIb for the alphaIIbbeta3 complex formation and provides an additional example of an apparently missense mutation causing a splicing defect.
Published: 2010

37. Cutting Edge: A Naturally Occurring Mutation in CD1e Impairs Lipid Antigen Presentation

Author: Sylvie Tourne, Blandine Maitre, Anthony Collmann, Emilie Layre, Sabrina Mariotti, François Signorino-Gelo, Caroline Loch, Jean Salamero, Martine Gilleron, Catherine Angénieux, Jean-Pierre Cazenave, Lucia Mori, Daniel Hanau, Germain Puzo, Gennaro De Libero, Henri de la Salle, Biologie des Cellules Dendritiques Humaines, EFS-Cancéropôle du Grand Est-Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology, University Hospital Basel [Basel], Institut de pharmacologie et de biologie structurale (IPBS), 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 génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires du transport intracellulaire, Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), EFS, Etablissement Français du Sang-Alsace, Biologie et pharmacologie de l'hémostase et de la thrombose, EFS-Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Biologie des cellules dendritiques humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), EFS-Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), and Peney, Maité
Subjects: MESH: Antigens, CD1, [SDV]Life Sciences [q-bio], medicine.disease_cause, Antigens, CD1, 0302 clinical medicine, Gangliosides, MESH: Glycolipids, Immunology and Allergy, MESH: Animals, ComputingMilieux_MISCELLANEOUS, Antigen Presentation, 0303 health sciences, Mutation, education.field_of_study, MESH: Amino Acid Substitution, 3. Good health, Cell biology, Protein Transport, Biochemistry, MESH: Protein Transport, MESH: Mutation, MESH: Cell Line, Tumor, Endosome, Immunology, Population, MESH: Glycoproteins, Endosomes, Biology, 03 medical and health sciences, Glycolipid, Immune system, Cell Line, Tumor, MESH: Polymorphism, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Beta (finance), education, Alleles, Glycoproteins, MESH: Gangliosides, 030304 developmental biology, Polymorphism, Genetic, MESH: Humans, MESH: Alleles, MESH: Clone Cells, Clone Cells, Amino Acid Substitution, MESH: Endosomes, MESH: Protein Processing, Post-Translational, MESH: Antigen Presentation, Gene polymorphism, Glycolipids, Protein Processing, Post-Translational, 030215 immunology
Abstract: The human CD1a–d proteins are plasma membrane molecules involved in the presentation of lipid Ags to T cells. In contrast, CD1e is an intracellular protein present in a soluble form in late endosomes or lysosomes and is essential for the processing of complex glycolipid Ags such as hexamannosylated phosphatidyl-myo-inositol, PIM6. CD1e is formed by the association of β2-microglobulin with an α-chain encoded by a polymorphic gene. We report here that one variant of CD1e with a proline at position 194, encoded by allele 4, does not assist PIM6 presentation to CD1b-restricted specific T cells. The immunological incompetence of this CD1e variant is mainly due to inefficient assembly and poor transport of this molecule to late endosomal compartments. Although the allele 4 of CD1E is not frequent in the population, our findings suggest that homozygous individuals might display an altered immune response to complex glycolipid Ags.
Published: 2008

38. Combinations of Cytochrome P450 Gene Polymorphisms Enhancing the Risk for Sporadic Colorectal Cancer Related to Red Meat Consumption

Author: Sébastien Küry, Louis-Dominique Chupin, Roger Faroux, Stéphane Bézieau, Bernard Lafraise, Sébastien Robiou-du-Pont, Jérémie Bourdon, Bruno Buecher, Tanguy Le Neel, Claire Le Houérou, Jean Ollivry, Véronique Sébille, Catherine Scoul, Hélène Colman, Biostatistique, Recherche Clinique et Mesures Subjectives en Santé, Université de Nantes (UN), Laboratoire d'Informatique de Nantes Atlantique (LINA), Centre National de la Recherche Scientifique (CNRS)-Mines Nantes (Mines Nantes)-Université de Nantes (UN), Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and Genetic Lab
Subjects: Male, Pathology, Epidemiology, MESH: Aryl Hydrocarbon Hydroxylases, Cohort Studies, MESH: Genotype, MESH: Aged, 80 and over, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Risk Factors, MESH: Risk Factors, Genotype, Medicine, MESH: Cohort Studies, Aged, 80 and over, MESH: Aged, MESH: Meat, Genetics, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Cytochrome P-450 CYP2E1, Middle Aged, MESH: Case-Control Studies, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, MESH: Cytochrome P-450 CYP1A2, Oncology, Red Meat Consumption, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, MESH: Cytochrome P-450 Enzyme System, Red meat, Female, Aryl Hydrocarbon Hydroxylases, France, Colorectal Neoplasms, Adult, medicine.medical_specialty, Meat, CYP1B1, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, MESH: Diet, Cytochrome P-450 CYP1A2, Humans, Genetic Predisposition to Disease, Genetic variability, Allele, Alleles, Aged, Cytochrome P-450 CYP2C9, 030304 developmental biology, MESH: Humans, business.industry, MESH: Alleles, Case-control study, MESH: Adult, MESH: Male, Diet, MESH: France, MESH: Cytochrome P-450 CYP2E1, Case-Control Studies, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, MESH: Female, MESH: Colorectal Neoplasms
Abstract: Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.−163A>C and c.1548T>C in CYP1A2, g.−1293G>C and g.−1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1460–7)
Published: 2007

39. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Author: Sarah K. Volkman, Lise Musset, Eric Legrand, Stanislaw J. Gabryszewski, Dyann F. Wirth, Béatrice Volney, Eli L. Moss, Stéphane Pelleau, Satish K. Dhingra, Daniel E. Neafsey, David A. Fidock, Jessica Casteras, Laboratoire de Parasitologie, Centre National de Référence du Paludisme - Région Antilles-Guyane, Institut Pasteur de la Guyane - Réseau International des Instituts Pasteur - WHO Collaborating Center for Surveillance of Antimalarial Drug Resistance, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Broad Institute of MIT and Harvard, Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, Harvard School of Public Health, This work was supported by European Commission Grant REGPOT-CT-2011-285837-430 STRonGer (to S.P.), AgenceNationale de la Recherche Investissements d’Avenir Grant ANR-10-LABX-25-01(to S.P. and L.M.), NIH Grants R01AI50234 (to D.A.F.) and R01AI109023 (to D.A.F.),and the Institut de Veille Sanitaire. Sequencing was supported, in part, byNational Institute of Allergy and Infectious Diseases, NIH, Department ofHealth and Human Services Contract HHSN272200900018C., ANR-10-LABX-25-01/10-LABX-0025, CEBA, CEnter of the study of Biodiversity in Amazonia(2010), European Project : 285837, EC:FP7:REGPOT, FP7-REGPOT-2011-1, STRONGER(2011), Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR - laboratoire associé), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Columbia University College of Physicians and Surgeons, ANR-10-LABX-0025,CEBA,CEnter of the study of Biodiversity in Amazonia(2010), European Project: 285837,EC:FP7:REGPOT,FP7-REGPOT-2011-1,STRONGER(2011), Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR), and Centre National de Référence du Paludisme - Laboratoire de parasitologie [Cayenne, Guyane française] (CNR)
Subjects: [SDV]Life Sciences [q-bio], Protozoan Proteins, Drug resistance, MESH: Genetic Markers, MESH: Genotype, Chloroquine, Genotype, [SDV.SPEE] Life Sciences [q-bio]/Public Health and Epidemiology, MESH: Quinolines/chemistry, MESH: Inhibitory Concentration 50, Genetics, education.field_of_study, Multidisciplinary, biology, MESH: Chloroquine/therapeutic use, Biological Sciences, MESH: Malaria/drug therapy, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug, PfCRT, MESH: Plasmodium falciparum/drug effects, Population, Plasmodium falciparum, MESH: Plasmodium falciparum/genetics, malaria, MESH: Membrane Transport Proteins/genetics, MESH: Phenotype, Evolution, Molecular, Piperaquine, evolution, MESH: Evolution, Molecular, MESH: French Guiana, parasitic diseases, medicine, Humans, MESH: Genome, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, education, MESH: Prevalence, MESH: Principal Component Analysis, drug resistance, MESH: Humans, MESH: Alleles, Membrane Transport Proteins, MESH: Retrospective Studies, MESH: Haplotypes, biology.organism_classification, medicine.disease, MESH: Protozoan Proteins/genetics, Mutation, MESH: Mutation, MESH: Drug Resistance/genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Malaria
Abstract: Comment in : Fusion of field studies and the laboratory solves a puzzle in antimalarial resistance. [Proc Natl Acad Sci U S A. 2015]; International audience; In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to
Published: 2015

40. Deafferentation in thalamic and pontine areas in severe traumatic brain injury

Author: Salma Mesmoudi, M. Laouchedi, Arnaud Messé, Damien Galanaud, F. Oulebsir Boumghar, Habib Benali, Louis Puybasset, Christine Delmaire, Sara Fernandez-Vidal, Mélanie Pélégrini-Issac, Vincent Perlbarg, Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Service de Neuroradiologie [CHU Pitié-Salpêtrière], 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), Services de neuroradiologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipement d'excellence MATRICE, Université Paris 1 Panthéon-Sorbonne (UP1), Laboratoire d'Imagerie Biomédicale (LIB), Johns Hopkins University School of Medicine [Baltimore], Colliot, Olivier, Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Laboratoire d'Imagerie Biomédicale [Paris] (LIB)
Subjects: Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Diffuse Axonal Injury, Reticular formation, MESH: Magnetic Resonance Imaging, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Thalamus, Pons, MESH: Child, MESH: DNA-Directed DNA Polymerase, Medicine, MESH: Aged, MESH: Middle Aged, Radiological and Ultrasound Technology, MESH: Infant, Newborn, Minimally conscious state, MESH: Mitochondrial Diseases, White Matter, MESH: Infant, MESH: Reproducibility of Results, Diffusion Tensor Imaging, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], MESH: Young Adult, Anesthesia, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Biomarker (medicine), Female, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Tractography, Adult, MESH: Mutation, Traumatic brain injury, MESH: Mitochondria, Sensitivity and Specificity, Image Interpretation, Computer-Assisted, MESH: Electroencephalography, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Radiology, Nuclear Medicine and imaging, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, MESH: Adolescent, MESH: Humans, business.industry, MESH: Alleles, MESH: Child, Preschool, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Reproducibility of Results, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], MESH: Adult, MESH: Electrodiagnosis, medicine.disease, MESH: Central Nervous System Diseases, MESH: Male, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, nervous system, Neurology (clinical), business, MESH: Female, Diffusion MRI
Abstract: International audience; Severe traumatic brain injury (TBI) is characterized mainly by diffuse axonal injuries (DAI). The cortico-subcortical disconnections induced by such fiber disruption play a central role in consciousness recovery. We hypothesized that these cortico-subcortical deafferentations inferred from diffusion MRI data could differentiate between TBI patients with favorable or unfavorable (death, vegetative state, or minimally conscious state) outcome one year after injury. Cortico-subcortical fiber density maps were derived by using probabilistic tractography from diffusion tensor imaging data acquired in 24 severe TBI patients and 9 healthy controls. These maps were compared between patients and controls as well as between patients with favorable (FO) and unfavorable (UFO) 1-year outcome to identify the thalamo-cortical and ponto-thalamo-cortical pathways involved in the maintenance of consciousness. Thalamo-cortical and ponto-thalamo-cortical fiber density was significantly lower in TBI patients than in healthy controls. Comparing FO and UFO TBI patients showed thalamo-cortical deafferentation associated with unfavorable outcome for projections from ventral posterior and intermediate thalamic nuclei to the associative frontal, sensorimotor and associative temporal cortices. Specific ponto-thalamic deafferentation in projections from the upper dorsal pons (including the reticular formation) was also associated with unfavorable outcome. Fiber density of cortico-subcortical pathways as measured from diffusion MRI tractography is a relevant candidate biomarker for early prediction of one-year favorable outcome in severe TBI.
Published: 2015

41. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Author: Debette, Stéphanie, Kamatani, Yoichiro, Wolf, Christiane, Agabiti Rosei, Enrico, Lanfranconi, Silvia, Ferrarese, Carlo, Susani, Emanuela, Bicocca, Milano, Giacalone, Giacomo, Paolucci, Stefano, Palmirotta, Raffaele, Paciaroni, Maurizio, Ballabio, Elena, Dittrich, Ralf, Parati, Eugenio A, Ciusani, Emilio, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Amort, Margareth, Bevan, Steve, James, Tom, Olsson, Sandra, Holmegaard, Lukas, Touzé, Emmanuel, Altintas, Ayse, Martin, Juan José, Kittner, Steven, MItchell, Braxton, Stine, Colin, O'Connell, Jeff, Dueker, Nicole, Koudstaal, Peter J, de Lau, Lonneke M L, Hofman, Albert, Southerland, Andrew M, Verhaaren, Benjamin F, Uitterlinden, Andre G, Montaner, Joan, Mendioroz, Maite, Yadav, Sunaina, Khan, Muhammad Saleem, Wilder, Michael, van Dijk, Ewoud, Maaijwee, Noortje, Rutten-Jacobs, Loes, Samson, Yves, Kramer, Jamie, Malik, Shaneela, Brott, Thomas G, Brown, Robert D, Singleton, Andrew, Hardy, John, Rich, Stephen S, Tanislav, Christian, Jungehülsing, Jan, Abboud, Shérine, Béjot, Yannick, Caso, Valeria, Bersano, Anna, Gschwendtner, Andreas, Metso, Tiina M, Sessa, Maria, Cole, John, Lamy, Chantal, Medeiros, Elisabeth, Beretta, Simone, Bonati, Leo H, Grau, Armin J, Michel, Patrik, Majersik, Jennifer J, Sharma, Pankaj, Kloss, Manja, Kalashnikova, Ludmila, Nazarova, Maria, Dobrynina, Larisa, Bartels, Eva, Guillon, Benoit, van den Herik, Evita G, Fernandez-Cadenas, Israel, Jood, Katarina, Nalls, Michael A, De Leeuw, Frank-Erik, Chauhan, Ganesh, Jern, Christina, Cheng, Yu-Ching, Werner, Inge, Metso, Antti J, Lichy, Christoph, Lyrer, Philippe A, Brandt, Tobias, Boncoraglio, Giorgio B, Wichmann, Heinz-Erich, Gieger, Christian, Engelter, Stefan T, Johnson, Andrew D, Böttcher, Thomas, Castellano, Maurizio, Arveiler, Dominique, Ikram, M Arfan, Breteler, Monique M B, Padovani, Alessandro, Meschia, James F, Kuhlenbäumer, Gregor, Rolfs, Arndt, Pezzini, Alessandro, Worrall, Bradford B, Consortium, International Stroke Genetics, Ringelstein, Erich-Bernd, Zelenika, Diana, Tatlisumak, Turgut, Lathrop, Mark, Leys, Didier, Amouyel, Philippe, Dallongeville, Jean, Group, CADISP, Thijs, Vincent, Lemmens, Robin, Pandolfo, Massimo, Bodenant, Marie, Louillet, Fabien, Mas, Jean-Louis, Deltour, Sandrine, Leder, Sara, Léger, Anne, Canaple, Sandrine, Godefroy, Olivier, Markus, Hugh S, Giroud, Maurice, Jacquin, Agnès, Moulin, Thierry, Vullier, Fabrice, Tzourio, Christophe, Dos Santos, Michael, Malik, Rainer, Hausser, Ingrid, Thomas-Feles, Constanze, Weber, Ralf, Dichgans, Martin, Grond-Ginsbach, Caspar, Hacke, Werner, Giossi, Alessia, Volonghi, Irene, Costa, Paolo, del Zotto, Elisabetta, Morotti, Andrea, Poli, Loris, Lorenza Muiesan, Maria, Salvetti, Massimo, Epidémiologie des maladies chroniques: impact des intéractions gène environnement sur la santé des populations, 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, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Helsinki University Central Hospital [Finland] (HUCH), Heidelberg University Hospital [Heidelberg], University Hospital Basel [Basel], Università degli Studi di Brescia = University of Brescia (UniBs), University Hospitals Leuven [Leuven], Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), University of Cambridge [UK] (CAM), Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), Ludwig-Maximilians-Universität München (LMU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), University of Virginia, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neurochirurgie Expérimentale [Brussels] (ULB 257), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Perugia = University of Perugia (UNIPG), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Ospedale San Raffaele, University of Maryland School of Medicine, University of Maryland System, Service de neurologie [Amiens], CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Klinikum Ludwigshafen [Germany], Service of Neurology [CHUV, Lausanne, Switzerland], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Utah School of Medicine [Salt Lake City], Institute of Cardiovascular Research (ICR2UL), Royal Holloway [University of London] (RHUL), Ashford and St Peter's hospitals NHS foundation trust, Russian Academy of Sciences [Moscow] (RAS), Centre for Cognition and Decision Making [HSE, Moscow], Institut of Cognitive Neuroscience [HSE, Moscow] (ICN), Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE)-Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE), Zentrum für neurologische Gefäßdiagnostik - Center for Neurological Vascular Diagnostics [Munich, Germany], Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Department of Neurology [Erasmus MC, Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital Universitario Mutua de Terrassa, Vall d'Hebron University Hospital [Barcelona], Insitute of Neuroscience and Physiology, University of Gothenburg (GU), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Schmieder Klinik [Heidelberg, Germany], Helmholtz Zentrum München = German Research Center for Environmental Health, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University Hospital Rostock, Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie, Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Brescia, Mayo Clinic [Jacksonville], Institute of Experimental Medicine - Institut für Experimentelle Medizin [Kiel, Germany] (IEM), Christian-Albrechts-Universität zu Kiel (CAU), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, McGill University and Genome Quebec Innovation Centre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Pharmacologie de la mort neuronale et de la plasticité cérébrale, IFR114-Université de Lille, Droit et Santé, Réseau International des Instituts Pasteur (RIIP), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, The CADISP study has been supported by INSERM, Lille 2 University, Institut Pasteur de Lille and Lille University Hospital and received funding from the European Regional Development Fund (FEDER funds) and Région Nord-Pas-de-Calais in the framework of Contrat de Projets Etat-Region 2007–2013 Région Nord-Pas-de-Calais (grant 09120030), Centre National de Génotypage, the Emil Aaltonen Foundation, the Paavo Ilmari Ahvenainen Foundation, the Helsinki University Central Hospital Research Fund, the Helsinki University Medical Foundation, the Päivikki and Sakari Sohlberg Foundation, the Aarne Koskelo Foundation, the Maire Taponen Foundation, the Aarne and Aili Turunen Foundation, the Lilly Foundation, the Alfred Kordelin Foundation, the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Foundation, the Finnish Brain Foundation, the Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique Régional, Fondation de France, Génopôle de Lille, Adrinord, the Basel Stroke Funds, the Käthe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences and the Swiss Heart Foundation.L.H.B., S.T.E. and P.A.L. were supported, in part, by a grant from the Swiss National Science Foundation (33CM30-124119). S.D. is supported by a Chair of Excellence from the French National Research Agency (ANR). S.D. and M.D. are supported by a grant from the Leducq Foundation. M.D. is supported by the Vascular Dementia Research Foundation. I.F.-C. is supported by the Miguel Servet programme (CP12/03298) from the Spanish Ministry of Health (Instituto de Salud Carlos III). G.K. is a member of the Deutsche Forschungsgemeinschaft Cluster of Excellence 'Inflammation at Interfaces'. P.S. is supported by a Department of Health (UK) senior fellowship. A.M.S. is supported by the American Heart Association/American Stroke Association National Clinical Research Program (AHA 3CRP14140001). V.T. is supported by Fonds Wetenschappelijk Onderzoek Flanders., CADISP Group, RIKEN Center for Integrative Medical Science, Università degli Studi di Brescia [Brescia], University of Virginia [Charlottesville], Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpêtrière]], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Neurologie Expérimentale [ULB, Brussels, Belgium] (ULB 257), Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Università degli Studi di Perugia (UNIPG), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), National Research University Higher School of Economics [Moscow] (HSE)-National Research University Higher School of Economics [Moscow] (HSE), Radboud university [Nijmegen], Helmholtz-Zentrum München (HZM), Westfälische Wilhelms-Universität Münster (WWU), The authors thank the staff and participants of all CADISP centers for their important contributions., Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpétriêre], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Erasmus MC other, Epidemiology, Debette, S, Kamatani, Y, Metso, T, Kloss, M, Chauhan, G, Engelter, S, Pezzini, A, Thijs, V, Markus, H, Dichgans, M, Wolf, C, Dittrich, R, Touzé, E, Southerland, A, Samson, Y, Abboud, S, Béjot, Y, Caso, V, Bersano, A, Gschwendtner, A, Sessa, M, Cole, J, Lamy, C, Medeiros, E, Beretta, S, Bonati, L, Grau, A, Michel, P, Majersik, J, Sharma, P, Kalashnikova, L, Nazarova, M, Dobrynina, L, Bartels, E, Guillon, B, Van Den Herik, E, Fernandez Cadenas, I, Jood, K, Nalls, M, De Leeuw, F, Jern, C, Cheng, Y, Werner, I, Metso, A, Lichy, C, Lyrer, P, Brandt, T, Boncoraglio, G, Wichmann, H, Gieger, C, Johnson, A, Böttcher, T, Castellano, M, Arveiler, D, Ikram, M, Breteler, M, Padovani, A, Meschia, J, Kuhlenbäumer, G, Rolfs, A, Worrall, B, Ringelstein, E, Zelenika, D, Tatlisumak, T, Lathrop, M, Leys, D, Amouyel, P, Dallongeville, J, Lemmens R, P, and Ferrarese, C
Subjects: Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myocardial Infarction, Genome-wide association study, Carotid Artery, Internal, Dissection, Gastroenterology, epidemiology [Carotid Artery, Internal, Dissection], Brain Ischemia, 0302 clinical medicine, Migraine Disorder, Odds Ratio, Finland, Vertebral Artery Dissection, 0303 health sciences, education.field_of_study, epidemiology [Hypercholesterolemia], MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Phactr-1 protein, human, MESH: Brain Ischemia, MESH: Follow-Up Studies, 3. Good health, MESH: Myocardial Infarction, Human, medicine.medical_specialty, Migraine Disorders, Hypercholesterolemia, MESH: Vertebral Artery Dissection, Lower risk, genetics [Brain Ischemia], Article, Follow-Up Studie, MESH: Carotid Artery, Internal, Dissection, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, genetics [Carotid Artery, Internal, Dissection], Genetics, Genetic predisposition, epidemiology [Brain Ischemia], Humans, epidemiology [Vertebral Artery Dissection], Polymorphism, education, Alleles, MESH: Humans, genetics [Vertebral Artery Dissection], MESH: Adult, Odds ratio, Microfilament Protein, medicine.disease, Adult, Female, Follow-Up Studies, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Hypertension, Microfilament Proteins, Middle Aged, Obesity, Risk Factors, Polymorphism, Single Nucleotide, MESH: Genome-Wide Association Study, Carotid Artery, MESH: Female, 030217 neurology & neurosurgery, epidemiology [Finland], Cervical Artery, Vertebral artery dissection, epidemiology [Hypertension], MESH: Hypertension, MESH: Risk Factors, MESH: Obesity, Stroke, Allele, Dissection, MESH: Finland, MESH: Genetic Predisposition to Disease, MESH: Hypercholesterolemia, Single Nucleotide, MESH: Migraine Disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], epidemiology [Myocardial Infarction], [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Population, MESH: Genetic Pleiotropy, physiology [Microfilament Proteins], Biology, MESH: Microfilament Proteins, Internal medicine, ddc:570, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 030304 developmental biology, epidemiology [Obesity], Risk Factor, MESH: Alleles, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Internal, MESH: Odds Ratio, MESH: Male, epidemiology [Migraine Disorders], genetics [Microfilament Proteins]
Abstract: Item does not contain fulltext Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 x 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 x 10(-3); combined P = 1.00 x 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
Published: 2015

42. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation

Author: Nahal Mansouri, Bertrand Boisson, Xianqin Zhang, Qing Kenneth Wang, Gillian I. Rice, Xing Wang, Seyed Alireza Mahdaviani, Chao Yuan, Yuval Itan, Flore Rozenberg, Satoshi Okada, Gilles Uzé, Dusan Bogunovic, Mugen Liu, Tao Ma, Pierre Lebon, Lilliana Radoshevich, Jingyu Liu, Wenqiang Liu, Tiantian Han, Davood Mansouri, Delin Liu, Jean-Laurent Casanova, Béatrice Payelle-Brogard, Yanick J. Crow, Dilek Yalnizoglu, Stefano Volpi, Zhi Li, Ozden Sanal, Lu Zeng, Bo Wang, Chunyuan Chen, Sandra Pellegrini, Shen-Ying Zhang, Emmanuelle Jouanguy, Luigi D. Notarangelo, Adolfo García-Sastre, Philippe Gros, Hui Jiang, Stéphanie Boisson-Dupuis, Véronique Francois-Newton, Laurent Abel, Scott D. Speer, Ilhan Tezcan, Jacinta Bustamante, Li, Zhi, Host and microbial molecular dissection of pathogenesis and immunity in tuberculosis - HOMITB - - EC:FP7:HEALTH2008-11-01 - 2012-04-30 - 200732 - VALID, A system view on the differential activities of human type I interferons - IFNACTION - - EC:FP7:HEALTH2009-01-01 - 2012-12-31 - 223608 - VALID, Huazhong University of Science and Technology [Wuhan] (HUST), Signalisation des Cytokines, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Istituto Giannina Gaslini, Genova, Immunologia Clinica e Sperimentale, Ankara University School of Medicine [Turkey], University of Manchester [Manchester], Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Department of Mathematics [Nanjing], Nanjing University of Aeronautics and Astronautics [Nanjing] (NUAA), Institut de Recherche en Communications Optiques et Microondes (IRCOM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Hunan Institute of Science and Technology, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de Physique des Particules (ex SPP) (DPhP), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Virologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Service de virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Università degli Studi di Brescia = University of Brescia (UniBs), The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the French National Agency for Research (ANR), the EU grant HOMITB (HEALTH-F32008-200732), the St Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health grant number 8UL1TR000043, the Rockefeller University, the National Institute of Allergy and Infectious Diseases grant number R37AI095983, Institut Merieux research grant and the Empire State Stem Cell fund through NYSDOH Contract #C023046 to Flow Cytometry Research Core at the Rockefeller University. The Cytokine Signaling Unit is supported by the Institut Pasteur, CNRS and INSERM. S.P. and G.U. received funding from the EU Seventh Framework Programme under grant agreement 223608. V.F.-N. was supported by the Ligue contre le Cancer. L.R. is a Human Frontier Science Program long-term fellow. L.D.N. was supported by the National Institute of Allergy and Infectious Diseases grant number 1PO1AI076210-01A1. Y.J.C. thanks the Manchester Biomedical Research Centre and the Greater Manchester Comprehensive Local Research Network, the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779, and the European Research Council (GA 309449). A.G.-S. acknowledges NIAID grants U19AI083025 and P01AI090935 for support. We thank C. Daussy for technical assistance, E. Bianchi and F. Michel for discussions. We thank D. Zhang and the members of the Zhang laboratory for assistance, advice and discussions. This work was supported by Chinese National Natural Science Foundation grants (81000079, 81170165) to X.Z. D.B. is supported by the National Institute of Allergy and Infectious Diseases grant number R00AI106942-02., European Project: 200732,EC:FP7:HEALTH,FP7-HEALTH-2007-A,HOMITB(2008), European Project: 223608,EC:FP7:HEALTH,FP7-HEALTH-2007-B,IFNACTION(2009), Çocuk ve Ergen Ruh Sağlığı ve Hastalıkları, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Shahid Beheshti University of Medical Sciences, The Rockefeller University, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Department of Mathematics (Nanjing University of Aeronautics and Astronautics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Département de Physique des Particules (ex SPP) (DPP), CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Saint-Vincent de Paul, Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Brescia [Brescia], and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1)
Subjects: Male, MESH: Signal Transduction, MESH: Inflammation, MESH: Interferon Type I, Intracellular Space, 0302 clinical medicine, Interferon, MESH: Child, Child, MESH: Endopeptidases, S-Phase Kinase-Associated Proteins, 0303 health sciences, MESH: Cytokines, Multidisciplinary, Effector, MESH: Gene Expression Regulation, Pedigree, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Interferon Type I, Viruses, Cytokines, Science & Technology - Other Topics, MESH: Intracellular Space, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Signal transduction, MESH: S-Phase Kinase-Associated Proteins, Ubiquitin Thiolesterase, Intracellular, Signal Transduction, medicine.drug, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Pedigree, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Viruses, 03 medical and health sciences, Immunity, Endopeptidases, medicine, Humans, MESH: Ubiquitins, Ubiquitins, Alleles, 030304 developmental biology, Inflammation, MESH: Adolescent, MESH: Humans, MESH: Alleles, Ubiquitination, ISG15, MESH: Male, Neuroimmunology, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, MESH: Ubiquitination, MESH: Female, Interferon type I
Abstract: Intracellular ISG15 is an interferon (IFN)-alpha/beta-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-alpha/beta-dependent antiviral immunity in mice(1-4). We previously published a study describing humans with inherited ISG15deficiency but without unusually severe viral diseases(5). We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-gamma-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-alpha/beta immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutieres syndrome and spondyloenchondrodysplasia(6-9). We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18(10,11), a potent negative regulator of IFN-alpha/beta signalling, resulting in the enhancement and amplification of IFN-alpha/beta responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-alpha/beta immunity. In humans, intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation.
Published: 2015

43. Eosinophilia predicts poor clinical outcomes in recent-onset arthritis: results from the ESPOIR cohort

Author: Dewi Guellec, Gabriel J. Tobón, Morgane Milin, Divi Cornec, Gilles Chiocchia, Alain Saraux, Valérie Devauchelle-Pensec, Olivier Vittecocq, Sandrine Jousse-Joulin, Thierry Marhadour, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Department of Internal Medicine (Dep Med - Div Rheum - CALI), Fundacion Vallee del Lili, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocyte B et Auto-immunité (LBAI), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: Pathology, MESH: Osteopontin, Inflammatory arthritis, [SDV]Life Sciences [q-bio], Arthritis, DMARDs (biologic), Early Arthritis, 0302 clinical medicine, Early Rheumatoid Arthritis, Immunology and Allergy, Medicine, Eosinophilia, MESH: Autoantibodies, 0303 health sciences, MESH: Arthritis, Rheumatoid, MESH: Peptides, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, respiratory system, MESH: Case-Control Studies, 3. Good health, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Cohort, medicine.symptom, DMARDs (synthetic), Cohort study, medicine.medical_specialty, Visual analogue scale, Immunology, Rheumatoid Arthritis, 03 medical and health sciences, Rheumatology, Internal medicine, 030304 developmental biology, 030203 arthritis & rheumatology, MESH: Humans, business.industry, MESH: Alleles, MESH: Macrophages, MESH: Haplotypes, Eosinophil, medicine.disease, MESH: Male, business, MESH: Citrulline, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Objectives To determine the prevalence of eosinophilia in patients with recent-onset arthritis suggestive of rheumatoid arthritis (RA) and to describe their features and outcomes. Methods We performed an ancillary study of data from a French prospective multicentre cohort study monitoring clinical, laboratory and radiographic data in patients with inflammatory arthritis of 6 weeks to 6 months duration. We determined the proportion of patients with eosinophilia, defined as a count >500/mm3, at baseline and after 3 years. Features of patients with and without baseline eosinophilia were compared. Results Baseline eosinophilia was evidenced in 26 of 804 (3.2%) patients; their mean eosinophil count was 637.7±107/mm3. Baseline eosinophilia was ascribed to atopic syndrome in 6 of 26 (23.1%) patients. After 3 years, patients with eosinophilia had higher Health Assessment Questionnaire scores (0.9 vs 0.5, p=0.004), higher patient visual analogue scale activity score and morning stiffness intensity (p=0.05), and were more often taking disease-modifying antirheumatic drugs (p=0.02). Baseline eosinophilia was not associated with presence of extra-articular manifestations. Conclusions Eosinophilia is rare in recent-onset arthritis suggestive of RA, and is usually directly related to the rheumatic disease. Our data suggest that patients with mild eosinophilia at diagnosis could respond worse to the treatment than those without.
Published: 2015

44. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles

Author: Deborah Hoogstraten, Wibeke J. Van Leeuwen, J. G. M. Huijmans, Frédéric Coin, Jean-Marc Egly, Marieke van de Ven, Judith Jans, Wendy Toussaint, James R. Mitchell, Jaan-Olle Andressoo, H. Bing Thio, Gijsbertus T. J. van der Horst, Jan H.J. Hoeijmakers, Jan de Wit, Jan de Boer, Molecular Genetics, Clinical Genetics, Dermatology, Radiology & Nuclear Medicine, Toussaint, Jean-Luc, Department of Cell Biology and Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Genetics, Department of dermatology, Department of Experimental Radiology, This research was supported by the Netherlands Organization for Scientific Research (NWO) through the foundation of the Research Institute for Diseases of the Elderly, as well as grants from the National Institutes of Health (1PO1 AG17242-02), National Institute of Environmental Health Sciences (1UO1 ES011044), European Commission (QRTL-1999-02002), and the Dutch Cancer Society (EUR 99-2004). JRM was a fellow of the Damon Runyon Cancer Research Fund (DRG 1677)., and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
Subjects: Transcription, Genetic, Eukaryotes, Trichothiodystrophy, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Molecular Biology/Structural Biology, Compound heterozygosity, Test cross, Cockayne syndrome, Loss of heterozygosity, Mice, Progeria, 0302 clinical medicine, Lethal allele, MESH: Animals, Biology (General), Growth Disorders, Mammals, Genetics, 0303 health sciences, MESH: Transcription Factor TFIIH, General Neuroscience, Homozygote, Ichthyosis, MESH: Xeroderma Pigmentosum Group D Protein, MESH: Growth Disorders, Mus (Mouse), Null allele, Phenotype, Hemizygote, Synopsis, General Agricultural and Biological Sciences, MESH: Ichthyosis, MESH: Homozygote, Research Article, Xeroderma pigmentosum, Ultraviolet Rays, QH301-705.5, Evolution, MESH: Progeria, Genes, Recessive, Biology, MESH: Phenotype, Genetics/Genomics/Gene Therapy, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, Allele, MESH: Mice, Alleles, MESH: Genes, Recessive, Xeroderma Pigmentosum Group D Protein, 030304 developmental biology, MESH: DNA Damage, MESH: Humans, Genetic carrier, General Immunology and Microbiology, MESH: Alleles, MESH: Transcription, Genetic, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Mice, Inbred C57BL, MESH: Hair Diseases, Genes, Lethal, MESH: Ultraviolet Rays, MESH: Genes, Lethal, Hair Diseases, Transcription Factor TFIIH, 030217 neurology & neurosurgery, DNA Damage
Abstract: Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals., Effects of mutations in Xpd were investigated in mice. Compound heterozygotes of otherwise homozygous lethal alleles demonstrated interallelic complementation and partial phenotypic rescue of XPD-related disease symptoms.
Published: 2006

45. Banking or Bankrupting: Strategies for Sustaining the Economic Future of Public Cord Blood Banks

Author: Cristina Navarrete, Christophe Picard, Jeremy Magalon, Alexander R. Schmidt, Martin Maiers, Gregory Katz, Alexander Platz, Christian Chabannon, Pablo Rubinstein, Joanne Kurtzberg, Jérôme Larghero, Sandrine Katsahian, Colin Brown, Catherine Schramm, Inst. Ciencia Molecular, Universitat de València (UV), School of Geosciences [Edinburgh], University of Edinburgh, Université Paris Diderot - Paris 7 (UPD7), Unité de Biostatistiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Marseille (CRCM), 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), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Johns Hopkins University Applied Physics Laboratory [Laurel, MD] (APL), ESSEC Business School, Essec Business School, Vascular research center of Marseille ( VRCM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), National Marrow Donor Program, Carolinas Cord Blood Bank, NHS Cord Blood Bank, National Cord Blood Program, Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Paris, Assistance publique - Hôpitaux de Paris (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), DKMS Cord Blood Bank, 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), Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Duke University Medical Center, New York Blood Center, Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Multivariate analysis, Economics, [SDV]Life Sciences [q-bio], lcsh:Medicine, Cell Count, 030204 cardiovascular system & hematology, MESH: Genotype, 0302 clinical medicine, Economic viability, Ethnicity, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, lcsh:Science, Multidisciplinary, 1. No poverty, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Fetal Blood, 3. Good health, Blood, Cord blood, Financial sustainability, [SDV.IMM]Life Sciences [q-bio]/Immunology, France, MESH: Tunisia, Research Article, medicine.medical_specialty, MESH: Rh-Hr Blood-Group System, 03 medical and health sciences, medicine, Humans, Blood banks, MESH: Humans, business.industry, MESH: Polymorphism, Restriction Fragment Length, Public health, MESH: Alleles, lcsh:R, MESH: Polymerase Chain Reaction, MESH: Male, Multivariate logistic regression model, Transplantation, Money supply and banking, Haplotypes, lcsh:Q, business, Utilization rate, MESH: Female, Finance, 030215 immunology, Demography
Abstract: International audience; BackgroundCord blood is an important source of stem cells. However, nearly 90% of public cord blood banks have declared that they are struggling to maintain their financial sustainability and avoid bankruptcy. The objective of this study is to evaluate how characteristics of cord blood units influence their utilization, then use this information to model the economic viability and therapeutic value of different banking strategies.MethodsRetrospective analysis of cord blood data registered between January 1st, 2009 and December 31st, 2011 in Bone Marrow Donor Worldwide. Data were collected from four public banks in France, Germany and the USA. Samples were eligible for inclusion in the analysis if data on cord blood and maternal HLA typing and biological characteristics after processing were available (total nucleated and CD34+ cell counts). 9,396 banked cord blood units were analyzed, of which 5,815 were Caucasian in origin. A multivariate logistic regression model assessed the influence of three parameters on the CBU utilization rate: ethnic background, total nucleated and CD34+ cell counts. From this model, we elaborated a Utilization Score reflecting the probability of transplantation for each cord blood unit. We stratified three Utilization Score thresholds representing four different banking strategies, from the least selective (scenario A) to the most selective (scenario D). We measured the cost-effectiveness ratio for each strategy by comparing performance in terms of number of transplanted cord blood units and level of financial deficit.ResultsWhen comparing inputs and outputs over three years, Scenario A represented the most extreme case as it delivered the highest therapeutic value for patients (284 CBUs transplanted) along with the highest financial deficit (USD 5.89 million). We found that scenario C resulted in 219 CBUs transplanted with a limited deficit (USD 0.98 million) that charities and public health could realistically finance over the long term. We also found that using a pre-freezing level of 18 x 108 TNC would be the most cost-effective strategy for a public bank.ConclusionOur study shows that a swift transition from strategy A to C can play a vital role in preventing public cord blood banks worldwide from collapsing.
Published: 2014

46. Mutations of acetylcholinesterase which confer insecticide resistance in insect populations

Author: Didier Fournier, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: 0106 biological sciences, Insecticides, MESH: Enzyme Stability, Insecta, DNA Mutational Analysis, MESH: Base Sequence, Toxicology, medicine.disease_cause, 01 natural sciences, Substrate Specificity, Insecticide Resistance, chemistry.chemical_compound, MESH: Insects, Enzyme Stability, MESH: Animals, MESH: DNA Mutational Analysis, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Genetics, chemistry.chemical_classification, 0303 health sciences, Mutation, biology, Hydrolysis, General Medicine, Acetylcholinesterase, MESH: Hydrolysis, MESH: Mutation, MESH: Population Density, 03 medical and health sciences, medicine, Animals, MESH: Insecticide Resistance, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Gene, Alleles, 030304 developmental biology, Population Density, Base Sequence, MESH: Alleles, Point mutation, Active site, MESH: Acetylcholinesterase, MESH: Insecticides, 010602 entomology, Enzyme, chemistry, Acetylation, biology.protein, MESH: Substrate Specificity
Abstract: Resistance-modified acetylcholinesterases have been described in many insect species and sequencing of their genes has allowed several point mutations to be described. Most mutations line the active site gorge. Each mutation provides a specific resistance pattern: it confers resistance to one insecticide but may increase sensitivity to another. Most mutations alter hydrolysis of the substrate by decreasing the rate of enzyme deacetylation and by diminishing the stability of the enzyme. Mutations are often found in combination in the same protein. This has several consequences: it increases the level of resistance, it enlarges the spectrum of resistance and it may restore the catalytic efficiency of the enzyme. Natural populations are heterogeneous, composed of a mixture of different alleles.
Published: 2005

47. Testing for triallelism: analysis of six BBS genes in a Bardet–Biedl syndrome family cohort

Author: Solenne Caron, Didier Lacombe, Jean-Louis Mandel, Fabienne Perrin-Schmitt, Hélène Dollfus, Virginie Laurier, Morin Gilles, Sabine Sigaudy, Alain Verloes, Mureille Holder, Christian Brandt, Dominique Bonneau, Josseline Kaplan, Corinne Stoetzel, Pierre Bitoun, Mireille Cossée, Dominique Martin-Coignard, Anne-Françoise Besancon, Christian P. Hamel, Bruno Leheup, Haifa Hichri, Pierre Sarda, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chaire Génétique Humaine, and Collège de France (CdF (institution))
Subjects: Male, BBS2, BBS1, BBS7, Group II Chaperonins, MESH: Amino Acid Sequence, medicine.disease_cause, Compound heterozygosity, Cohort Studies, MESH: Genetic Screening, MESH: Bardet-Biedl Syndrome, MESH: Proteins, MESH: Cohort Studies, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Genetic Carrier Screening, 030305 genetics & heredity, MESH: Genetic Heterogeneity, Pedigree, Female, France, MESH: Molecular Chaperones, Microtubule-Associated Proteins, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH: Pedigree, Molecular Sequence Data, Biology, Genetic Heterogeneity, 03 medical and health sciences, Bardet–Biedl syndrome, MESH: Polymorphism, Genetic, medicine, Humans, Amino Acid Sequence, Genetic Testing, Allele, Bardet-Biedl Syndrome, Alleles, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Polymorphism, Genetic, MESH: Molecular Sequence Data, MESH: Humans, MESH: Heterozygote Detection, Genetic heterogeneity, MESH: Alleles, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, MESH: France, Cytoskeletal Proteins, MESH: Microsatellite Repeats, MESH: Female, Microsatellite Repeats, Molecular Chaperones
Abstract: International audience; The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n=2), or associated with another mutation at BBS1 (n=3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes.
Published: 2005

48. The Caenorhabditis elegans unc-63 Gene Encodes a Levamisole-sensitive Nicotinic Acetylcholine Receptor α Subunit

Author: Janet E. Richmond, James A. Lewis, M. D. Squire, J. T. Fleming, David B. Sattelle, Andrew K. Jones, Emmanuel Culetto, Howard A. Baylis, Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Muscles, MESH: Sequence Analysis, DNA, MESH: Sequence Homology, Amino Acid, MESH: Neurons, MESH: Amino Acid Sequence, Receptors, Nicotinic, Biochemistry, MESH: Nucleic Acid Hybridization, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Animals, MESH: Models, Genetic, Transgenes, Cloning, Molecular, MESH: Phylogeny, Peptide sequence, Phylogeny, Caenorhabditis elegans, Cellular localization, Neurons, 0303 health sciences, MESH: Electrophysiology, biology, MESH: Peptides, Antinematodal Agents, Muscles, Nucleic Acid Hybridization, MESH: Caenorhabditis elegans Proteins, Electrophysiology, Nicotinic acetylcholine receptor, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.anatomical_structure, MESH: Receptors, Nicotinic, MESH: Mutation, DNA, Complementary, Molecular Sequence Data, MESH: Transgenes, macromolecular substances, Neuromuscular junction, 03 medical and health sciences, MESH: Levamisole, In vivo, MESH: Caenorhabditis elegans, medicine, Animals, MESH: Cloning, Molecular, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Caenorhabditis elegans Proteins, Molecular Biology, Gene, Alleles, 030304 developmental biology, MESH: Molecular Sequence Data, Models, Genetic, Sequence Homology, Amino Acid, MESH: Alleles, fungi, MESH: DNA, Complementary, Sequence Analysis, DNA, Cell Biology, biology.organism_classification, Molecular biology, Protein Structure, Tertiary, Levamisole, nervous system, Mutation, Peptides, MESH: Antinematodal Agents, 030217 neurology & neurosurgery, Genetic screen
Abstract: The anthelmintic drug levamisole causes hypercontraction of body wall muscles and lethality in nematode worms. In the nematode Caenorhabditis elegans, a genetic screen for levamisole resistance has identified 12 genes, three of which (unc-38, unc-29, and lev-1) encode nicotinic acetylcholine receptor (nAChR) subunits. Here we describe the molecular and functional characterization of another levamisole-resistant gene, unc-63, encoding a nAChR alpha subunit with a predicted amino acid sequence most similar to that of UNC-38. Like UNC-38 and UNC-29, UNC-63 is expressed in body wall muscles. In addition, UNC-63 is expressed in vulval muscles and neurons. We also show that LEV-1 is expressed in body wall muscle, thus overlapping the cellular localization of UNC-63, UNC-38, and UNC-29 and suggesting possible association in vivo. This is supported by electrophysiological studies on body wall muscle, which demonstrate that a levamisole-sensitive nAChR present at the C. elegans neuromuscular junction requires both UNC-63 and LEV-1 subunits. Thus, at least four subunits, two alpha types (UNC-38 and UNC-63) and two non-alpha types (UNC-29 and LEV-1), can contribute to levamisole-sensitive muscle nAChRs in nematodes.
Published: 2004

49. A Large-Scale Screen for Mutagen-Sensitive Loci in Drosophila

Author: Kenneth C. Burtis, Eszter K. Vladar, R. Scott Hawley, Anne Laurençon, Charisse M Orme, Nathan J. Harris, Sarah M. Wayson, Emmanuel P. Bakis, Heather K. Peters, David T. Harris, Sasha Langley, Christina L. Boulton, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA Repair, MESH: Sequence Homology, Amino Acid, [SDV]Life Sciences [q-bio], Mutant, MESH: Methyl Methanesulfonate, MESH: Amino Acid Sequence, MESH: Base Sequence, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, Nondisjunction, Genetic, MESH: Animals, Recombination, Genetic, MESH: DNA Repair, Genetics, MESH: Genetic Complementation Test, 0303 health sciences, Mutation, MESH: Mechlorethamine, biology, MESH: DNA, Chromosome Mapping, MESH: Nondisjunction, Genetic, MESH: Saccharomyces cerevisiae, 3. Good health, Meiosis, Drosophila melanogaster, Genetic Techniques, MESH: Recombination, Genetic, Research Article, MESH: Mutation, DNA repair, Molecular Sequence Data, Saccharomyces cerevisiae, MESH: Drosophila melanogaster, 03 medical and health sciences, MESH: Mutagens, medicine, Animals, Amino Acid Sequence, Mechlorethamine, Gene, Alleles, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Sequence Homology, Amino Acid, MESH: Alleles, Genetic Complementation Test, fungi, DNA, Methyl Methanesulfonate, biology.organism_classification, Molecular biology, Methyl methanesulfonate, MESH: Meiosis, MESH: Genetic Techniques, chemistry, MESH: Chromosome Mapping, Homologous recombination, 030217 neurology & neurosurgery, Mutagens
Abstract: In a screen for new DNA repair mutants, we tested 6275 Drosophila strains bearing homozygous mutagenized autosomes (obtained from C. Zuker) for hypersensitivity to methyl methanesulfonate (MMS) and nitrogen mustard (HN2). Testing of 2585 second-chromosome lines resulted in the recovery of 18 mutants, 8 of which were alleles of known genes. The remaining 10 second-chromosome mutants were solely sensitive to MMS and define 8 new mutagen-sensitive genes (mus212–mus219). Testing of 3690 third chromosomes led to the identification of 60 third-chromosome mutants, 44 of which were alleles of known genes. The remaining 16 mutants define 14 new mutagen-sensitive genes (mus314–mus327). We have initiated efforts to identify these genes at the molecular level and report here the first two identified. The HN2-sensitive mus322 mutant defines the Drosophila ortholog of the yeast snm1 gene, and the MMS- and HN2-sensitive mus301 mutant defines the Drosophila ortholog of the human HEL308 gene. We have also identified a second-chromosome mutant, mus215ZIII-2059, that uniformly reduces the frequency of meiotic recombination to
Published: 2004

50. Phenotypic Analysis of Separation-of-Function Alleles of MEI-41, Drosophila ATM/ATR

Author: R. Scott Hawley, Jeff Sekelsky, Anne Laurençon, Amanda Purdy, Tin Tin Su, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon)
Subjects: Male, MESH: Signal Transduction, MESH: Sequence Analysis, DNA, Cell cycle checkpoint, MESH: Sequence Homology, Amino Acid, MESH: Drosophila, [SDV]Life Sciences [q-bio], MESH: Methyl Methanesulfonate, Cell Cycle Proteins, MESH: Cell Cycle, Eukaryotic DNA replication, MESH: Amino Acid Sequence, MESH: Base Sequence, medicine.disease_cause, MESH: Structure-Activity Relationship, 0302 clinical medicine, Drosophila Proteins, MESH: Animals, MESH: Models, Genetic, Phosphorylation, MESH: Phylogeny, Phylogeny, MESH: Heterozygote, Recombination, Genetic, Genetics, 0303 health sciences, Mutation, Cell Cycle, Cell cycle, MESH: Crosses, Genetic, Null allele, DNA-Binding Proteins, Phenotype, Drosophila, Female, MESH: Recombination, Genetic, Drosophila Protein, Signal Transduction, Research Article, Heterozygote, X Chromosome, MESH: Mutation, MESH: Drosophila Proteins, Blotting, Western, Molecular Sequence Data, Mitosis, Protein Serine-Threonine Kinases, Biology, MESH: Phenotype, MESH: Protein-Serine-Threonine Kinases, Structure-Activity Relationship, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Mutagens, medicine, Animals, MESH: Blotting, Western, Amino Acid Sequence, CHEK1, Metaphase, Alleles, Crosses, Genetic, 030304 developmental biology, MESH: DNA Damage, MESH: Molecular Sequence Data, MESH: X Chromosome, Base Sequence, Dose-Response Relationship, Drug, Models, Genetic, Sequence Homology, Amino Acid, MESH: Phosphorylation, MESH: Alleles, MESH: Fertility, Sequence Analysis, DNA, MESH: Mitosis, Methyl Methanesulfonate, MESH: Male, Fertility, MESH: Gene Deletion, DNA Transposable Elements, MESH: Female, Gene Deletion, 030217 neurology & neurosurgery, DNA Damage, Mutagens
Abstract: ATM/ATR kinases act as signal transducers in eukaryotic DNA damage and replication checkpoints. Mutations in ATM/ATR homologs have pleiotropic effects that range from sterility to increased killing by genotoxins in humans, mice, and Drosophila. Here we report the generation of a null allele of mei-41, Drosophila ATM/ATR homolog, and the use of it to document a semidominant effect on a larval mitotic checkpoint and methyl methanesulfonate (MMS) sensitivity. We also tested the role of mei-41 in a recently characterized checkpoint that delays metaphase/anaphase transition after DNA damage in cellular embryos. We then compare five existing mei-41 alleles to the null with respect to known phenotypes (female sterility, cell cycle checkpoints, and MMS resistance). We find that not all phenotypes are affected equally by each allele, i.e., the functions of MEI-41 in ensuring fertility, cell cycle regulation, and resistance to genotoxins are genetically separable. We propose that MEI-41 acts not in a single rigid signal transduction pathway, but in multiple molecular contexts to carry out its many functions. Sequence analysis identified mutations, which, for most alleles, fall in the poorly characterized region outside the kinase domain; this allowed us to tentatively identify additional functional domains of MEI-41 that could be subjected to future structure-function studies of this key molecule.
Published: 2003

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