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

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333 results on '"MESH: Alleles"'

1. A long noncoding RNA influences the choice of the X chromosome to be inactivated

Author: Andreas Hierholzer, Corinne Chureau, Alessandra Liverziani, Nerea Blanes Ruiz, Bruce M. Cattanach, Alexander N. Young, Manish Kumar, Andrea Cerase, Phil Avner, European Molecular Biology Laboratory [Rome] (EMBL), Génomique et Epigénomique du Développement des Vertébrés - Genomics and Epigenomics of Vertebrates Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Queen Mary University of London (QMUL), and MRC Harwell Institute [UK]
Subjects: X Chromosome, [SDV]Life Sciences [q-bio], female mouse embryo, noncoding RNA, MESH: Mammals, Mice, pluripotency factors, Genetic, X Chromosome Inactivation, Dosage Compensation, Genetic, Animals, MESH: Animals, MESH: Mice, Alleles, Mammals, MESH: X Chromosome Inactivation, Multidisciplinary, MESH: Alleles, MESH: Dosage Compensation, Genetic, MESH: RNA, Long Noncoding, X chromosome inactivation, X-controlling element, Female, RNA, Long Noncoding, Dosage Compensation, RNA, Long Noncoding, MESH: Female
Abstract: X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element ( Xce ). Although the Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong Xce alleles we show that Lppnx modulates the expression of Xist lncRNA , one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of Xist . This effect is counteracted by enhanced binding of Rex1 in DxPas34 , another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong Xce alleles results from differential transcription factor binding of Xist Intron 1 and DxPas34 , and that Lppnx represents a decisive factor in explaining the action of the Xce .
Published: 2022

2. Functional consequences of archaic introgression and their impact on fitness

Author: Lluis Quintana-Murci, Maxime Rotival, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), The laboratory of L.Q.-M. is supported by the Institut Pasteur, the Collège de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10- LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), and the Fondation pour la Recherche Médicale (Equipe FRM DEQ20180339214)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Génomique humaine et évolution
Subjects: lcsh:QH426-470, Genetic Fitness, Adaptation, Biological, Introgression, Biology, Genetic Introgression, 03 medical and health sciences, 0302 clinical medicine, MESH: Genetic Fitness, MESH: Genetic Introgression, MESH: Epistasis, Genetic, Animals, Humans, MESH: Animals, lcsh:QH301-705.5, Alleles, MESH: Genome, Human, 030304 developmental biology, Neanderthals, MESH: Neanderthals, 0303 health sciences, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genome, Human, MESH: Adaptation, Biological, MESH: Alleles, Epistasis, Genetic, MESH: Haplotypes, lcsh:Genetics, Editorial, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Biology (General), Evolutionary biology, Epistasis, Adaptation, 030217 neurology & neurosurgery
Abstract: International audience; Anatomically modern humans started to exit Africa for the first time at least 60,000 years ago (ya). Along their journey across the globe, they encountered and admixed with other hominins that are now extinct, such as the Neanderthals or Denisovans. Given the deep divergence time between ancient hominins and modern humans, such admixture events left molecular traces in non-African populations that are still visible today in their genomes [1]. Over the past few years, there is accumulating evidence to suggest that these segments of “archaic” DNA have the potential to contribute to phenotypic differences between contemporary individuals and populations [2]. Yet, to understand the genuine contribution of archaic alleles to the genetic architecture of complex traits, it is necessary to account for the diverse selective pressures that have acted upon introgressed alleles. Here, we discuss recent findings on how natural selection—either negative or positive—has shaped the landscape of Neanderthal ancestry in the genomes of modern Eurasians, and comment on the contribution of archaic haplotypes to present-day phenotypic variation.
Published: 2020

3. bric à brac controls sex pheromone choice by male European corn borer moths

Author: Astrid T. Groot, Brad S. Coates, David G. Heckel, Melanie Unbehend, Teun Dekker, Fotini Koutroumpa, Erik B. Dopman, Genevieve M. Kozak, Max Planck Institute for Chemical Ecology, Max-Planck-Gesellschaft, Tufts University [Medford], University of Massachusetts [Dartmouth], University of Massachusetts System (UMASS), University of Amsterdam [Amsterdam] (UvA), Institut d'écologie et des sciences de l'environnement de Paris (iEES Paris ), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), USDA-ARS : Agricultural Research Service, Swedish University of Agricultural Sciences (SLU), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Evolutionary and Population Biology (IBED, FNWI)
Subjects: Male, 0106 biological sciences, 0301 basic medicine, MESH: Aldehyde Oxidoreductases, Linkage disequilibrium, European corn borer, Behavioural ecology, Speciation, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genes, Insect, MESH: Genes, Insect, Moths, 01 natural sciences, Linkage Disequilibrium, MESH: Insect Proteins, Inbreeding, MESH: Animals, Sex Attractants, MESH: Evolution, Molecular, Recombination, Genetic, Multidisciplinary, MESH: Moths, MESH: Transcription Factors, Aldehyde Oxidoreductases, MESH: Gene Expression Regulation, MESH: Mating Preference, Animal, MESH: Sex Attractants, MESH: Linkage Disequilibrium, Sex pheromone, Behavioural genetics, Insect Proteins, Pheromone, Female, MESH: Recombination, Genetic, Science, Quantitative Trait Loci, Locus (genetics), Biology, 010603 evolutionary biology, Article, Evolutionary genetics, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, 03 medical and health sciences, MESH: Inbreeding, MESH: Polymorphism, Genetic, Animals, Allele, Alleles, Evolutionary Biology, Polymorphism, Genetic, Human evolutionary genetics, MESH: Alleles, Assortative mating, General Chemistry, Mating Preference, Animal, biology.organism_classification, MESH: Male, MESH: Quantitative Trait Loci, 030104 developmental biology, Gene Expression Regulation, Evolutionary biology, MESH: Genome-Wide Association Study, MESH: Female, Genome-Wide Association Study, Transcription Factors
Abstract: The sex pheromone system of ~160,000 moth species acts as a powerful form of assortative mating whereby females attract conspecific males with a species-specific blend of volatile compounds. Understanding how female pheromone production and male preference coevolve to produce this diversity requires knowledge of the genes underlying change in both traits. In the European corn borer moth, pheromone blend variation is controlled by two alleles of an autosomal fatty-acyl reductase gene expressed in the female pheromone gland (pgFAR). Here we show that asymmetric male preference is controlled by cis-acting variation in a sex-linked transcription factor expressed in the developing male antenna, bric à brac (bab). A genome-wide association study of preference using pheromone-trapped males implicates variation in the 293 kb bab intron 1, rather than the coding sequence. Linkage disequilibrium between bab intron 1 and pgFAR further validates bab as the preference locus, and demonstrates that the two genes interact to contribute to assortative mating. Thus, lack of physical linkage is not a constraint for coevolutionary divergence of female pheromone production and male behavioral response genes, in contrast to what is often predicted by evolutionary theory., Many organisms, including moths, use pheromones to attract mates. A study using multiple genomic tools and gene editing identifies a new, neuronal gene underlying mate preference and shows that signal and response loci are in linkage disequilibrium despite being physically unlinked.
Published: 2021

4. 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

5. Monoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex

Author: Faria, Joana, Glover, Lucy, Hutchinson, Sebastian, Boehm, Cordula, Field, Mark C., Horn, David, University of Dundee, The work was funded by Wellcome Trust Investigator Awards to D.H. [100320/Z/12/Z] and M.C.F. [204697/Z/16/Z] with additional support from a Wellcome Trust Centre Award [203134/Z/16/Z]. The University of Dundee Flow Cytometry and Imaging Facilities are supported by a Wellcome Trust award [097418/Z/11/Z], and the MRC Next Generation Optical Microscopy award [MR/K015869/1], respectively, and while both the Proteomics and Imaging Facilities are supported by a Wellcome Trust Technology Platform award [097945/B/11/Z].
Subjects: DNA Replication, Transcription, Genetic, Science, [SDV]Life Sciences [q-bio], Trypanosoma brucei brucei, Protozoan Proteins, MESH: DNA Replication, MESH: Host-Parasite Interactions, Article, Cell Line, Epigenesis, Genetic, Host-Parasite Interactions, parasitic diseases, Parasite genetics, Animals, MESH: Animals, MESH: Epigenesis, Genetic, MESH: Immune Evasion, lcsh:Science, MESH: Protozoan Proteins, Alleles, Immune Evasion, MESH: Alleles, MESH: Transcription, Genetic, MESH: Trypanosoma brucei brucei, Gene silencing, MESH: Gene Expression Regulation, Antigenic Variation, MESH: Cell Line, Parasite biology, Chromatin Assembly Factor-1, MESH: Trypanosomiasis, African, Trypanosomiasis, African, Gene Expression Regulation, MESH: Antigenic Variation, MESH: Variant Surface Glycoproteins, Trypanosoma, lcsh:Q, Epigenetics analysis, MESH: Chromatin Assembly Factor-1, Variant Surface Glycoproteins, Trypanosoma
Abstract: The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy., Monoallelic expression of variant surface glycoprotein genes (VSGs) is essential for immune evasion by Trypanosoma brucei. Here, Faria et al. show that the VEX protein complex controls VSG allelic exclusion, and that CAF‐1 sustains inheritance of the VEX‐complex in association with the active VSG.
Published: 2019

6. 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

7. Factors that influence bidirectional long-tract homozygosis due to double-strand break repair in Candida albicans

Author: Murielle Chauvel, Adeline Feri, Corinne Maufrais, Mélanie Legrand, Christophe d'Enfert, Timea Marton, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics, Institut Pasteur [Paris] (IP), T.M. is the recipient of a Ph.D. fellowship from the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID) and Indo-French Centre for the Promotion of Advanced Research CEFIPRA (CEFIPRA). We acknowledge support from the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases [ANR10-LABX-62-IBEID]) and of the Indo-French Centre for the Promotion of Advanced Research CEFIPRA (CEFIPRA). A.F. was the recipient of a Ph.D. grant from INRA Jouy-en-Josas and Institut Pasteur., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: DNA Repair, [SDV]Life Sciences [q-bio], MESH: DNA Breaks, Double-Stranded, Loss of Heterozygosity, MESH: DNA Replication, MESH: DNA Breaks, chemistry.chemical_compound, MESH: Saccharomyces cerevisiae Proteins, 0302 clinical medicine, Mismatch Repair Pathway, Candida albicans, DNA Breaks, Double-Stranded, MESH: DNA Repair, Genetics, Gene Rearrangement, Recombination, Genetic, 0303 health sciences, Homozygote, MESH: Saccharomyces cerevisiae, MESH: Chromosomes, Fungal, Double Strand Break Repair, mitotic recombination, break induced replication, MESH: Recombination, Genetic, Chromosomes, Fungal, MESH: Homozygote, DNA Replication, MESH: Mutation, Mitotic crossover, Saccharomyces cerevisiae Proteins, MESH: Gene Rearrangement, DNA repair, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, Centromere, MESH: Diploidy, Gene, Alleles, 030304 developmental biology, MESH: Loss of Heterozygosity, Investigation, MESH: Alleles, MESH: Candida albicans, DNA Breaks, bidirectional loss-of-heterozygosity, biology.organism_classification, Diploidy, chemistry, Mutation, 030217 neurology & neurosurgery, DNA
Abstract: Genomic rearrangements have been associated with the acquisition of adaptive phenotypes, allowing organisms to efficiently generate new favorable genetic combinations. The diploid genome of Candida albicans is highly plastic, displaying numerous genomic rearrangements that are often the by-product of the repair of DNA breaks. For example, DNA double-strand breaks (DSB) repair using homologous-recombination pathways are a major source of loss-of-heterozygosity (LOH), observed ubiquitously in both clinical and laboratory strains of C. albicans. Mechanisms such as break-induced replication (BIR) or mitotic crossover (MCO) can result in long tracts of LOH, spanning hundreds of kilobases until the telomere. Analysis of I-SceI-induced BIR/MCO tracts in C. albicans revealed that the homozygosis tracts can ascend several kilobases towards the centromere, displaying homozygosis from the break site towards the centromere. We sought to investigate the molecular mechanisms that could contribute to this phenotype by characterizing a series of C. albicans DNA repair mutants, including pol32-/-, msh2-/-, mph1-/- and mus81-/-. The impact of deleting these genes on genome stability revealed functional differences between Saccharomyces cerevisiae (a model DNA repair organism) and C. albicans. Additionally, we demonstrated that ascending LOH tracts towards the centromere are associated with intrinsic features of BIR and potentially involve the mismatch repair pathway which acts upon natural heterozygous positions. Overall, this mechanistic approach to study LOH deepens our limited characterization of DNA repair pathways in C. albicans and brings forth the notion that centromere proximal alleles from DNA break sites are not guarded from undergoing LOH.
Published: 2020

8. 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

9. Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Author: Lluis Quintana-Murci, Antoine Favier, Franck Rapaport, David Neil Cooper, Peter D. Stenson, Etienne Patin, Laurent Abel, Jean-Laurent Casanova, Yufei Luo, Marie Lopez, Antonio Rausell, Yoann Seeleuthner, The Clinical Bioinformatics laboratory (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), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK, Howard Hughes Medical Institute (HHMI), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), The Laboratory of Clinical Bioinformatics was supported by the French National Research Agency (ANR)'Investissements d’Avenir'Program (Grant ANR-10-IAHU-01) and Christian Dior Couture, Dior. The Laboratory of Human Geneticsof Infectious Diseases was supported, in part, by grants from ANR under the'Investissements d’Avenir'Program (Grant ANR-10-IAHU-01), the Fondation pourla Recherche Médicale (Equipe FRM EQU201903007798), the St. Giles Foundation,and the Rockefeller University. The laboratory of L.Q.-M. is supported by theInstitut Pasteur, the Collège de France, the French Government’s Investissementsd’Avenir program, Laboratoires d’Excellence'Integrative Biology of Emerging Infectious Diseases'(Grant ANR-10-LABX-62-IBEID) and'Milieu Intérieur'(GrantANR-10-LABX-69-22701), and the Fondation pour la Recherche Médicale (EquipeFRM DEQ20180339214). D.N.C. and P.D.S. acknowledge the financial supportof Qiagen Inc. through a license agreement with Cardiff University., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-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), Cardiff University, Collège de France - Chaire Génomique humaine et évolution, PATIN, Etienne, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID
Subjects: Linkage disequilibrium, Pseudogene, Population, MESH: Human Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, 03 medical and health sciences, Negative selection, 0302 clinical medicine, MESH: Fucosyltransferases, Loss of Function Mutation, positive selection, Apolipoproteins L, Humans, MESH: Proteins, MESH: Genetic Variation, Allele, education, Gene, Loss function, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Sex Chromosomes, MESH: Humans, redundancy, MESH: Alleles, MESH: Apolipoproteins L, Homozygote, Genetic Variation, Proteins, negative selection, MESH: Sex Chromosomes, Human Genetics, MESH: Loss of Function Mutation, Biological Sciences, Fucosyltransferases, Phenotype, loss of function, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human genome, pseudogenization, 030217 neurology & neurosurgery, MESH: Homozygote
Abstract: Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the knownFUT2mutant allele conferring resistance to intestinal viruses and anAPOL3variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival.Significance statementHuman genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival.
Published: 2020

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

Author: Guéant, Jean-Louis, Chéry, Céline, Oussalah, Abderrahim, Nadaf, Javad, Coelho, David, Josse, Thomas, Flayac, Justine, Robert, Aurélie, Koscinski, Isabelle, Gastin, Isabelle, Filhine-Tresarrieu, Pierre, Pupavac, Mihaela, Brebner, Alison, Watkins, David, Pastinen, Tomi, Montpetit, Alexandre, Hariri, Fadi, Tregouët, David, Raby, Benjamin A, Chung, Wendy K., Morange, Pierre-Emmanuel, Froese, D. Sean, Baumgartner, Matthias R., Benoist, Jean-François, Ficicioglu, Can, Marchand, Virginie, Motorin, Yuri, Bonnemains, Chrystèle, Feillet, François, Majewski, Jacek, Rosenblatt, David S., GONNET, JULIE, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), McGill University = Université McGill [Montréal, Canada], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Harvard Medical School [Boston] (HMS), University of Missouri [Columbia] (Mizzou), University of Missouri System, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), University hospital of Zurich [Zurich], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia (CHOP ), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), McGill University, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], University of Missouri [Columbia], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition (C2VN), University of Pennsylvania [Philadelphia], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: MESH: Mutation, MESH: Metabolism, Inborn Errors, MESH: Pedigree, Science, MESH: Azacitidine, MESH: Peroxiredoxins, MESH: Carrier Proteins, MESH: Base Sequence, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Epistasis, Genetic, lcsh:Science, MESH: Heterozygote, MESH: Humans, MESH: Alleles, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Male, MESH: Vitamin B 12, MESH: Enzyme Inhibitors, MESH: Fibroblasts, MESH: Family Health, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:Q, MESH: Whole Genome Sequencing, MESH: Female
Abstract: To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios., Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.
Published: 2018

17. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019

18. 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

19. Genomic Imprinting and Physiological Processes in Mammals

Author: Valter Tucci, Anthony R. Isles, Gavin Kelsey, Anne C. Ferguson-Smith, Marisa S. Bartolomei, Nissim Benvenisty, Déborah Bourc’his, Marika Charalambous, Catherine Dulac, Robert Feil, Juliane Glaser, Lisa Huelsmann, Rosalind M. John, Gráinne I. McNamara, Kim Moorwood, Francoise Muscatelli, Hiroyuki Sasaki, Beverly I. Strassmann, Claudius Vincenz, Jon Wilkins, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: [SDV]Life Sciences [q-bio], MESH: Biological Evolution, MESH: Physiological Phenomena, Biology, General Biochemistry, Genetics and Molecular Biology, Chromosomes, MESH: Mammals, Epigenesis, Genetic, 03 medical and health sciences, Genomic Imprinting, 0302 clinical medicine, MESH: DNA Methylation, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, Epigenetics, MESH: Epigenesis, Genetic, Imprinting (psychology), Allele, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Alleles, Physiological Phenomena, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Epigenesis, Genetics, Mammals, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Alleles, DNA Methylation, Phenotype, Biological Evolution, MESH: Genomic Imprinting, Multicellular organism, DNA methylation, MESH: Chromosomes, Genomic imprinting, 030217 neurology & neurosurgery
Abstract: International audience; Complex multicellular organisms, such as mammals, express two complete sets of chromosomes per nucleus, combining the genetic material of both parents. However, epigenetic studies have demonstrated violations to this rule that are necessary for mammalian physiology; the most notable parental allele expression phenomenon is genomic imprinting. With the identification of endogenous imprinted genes, genomic imprinting became well-established as an epigenetic mechanism in which the expression pattern of a parental allele influences phenotypic expression. The expanding study of genomic imprinting is revealing a significant impact on brain functions and associated diseases. Here, we review key milestones in the field of imprinting and discuss mechanisms and systems in which imprinted genes exert a significant role.
Published: 2019

20. 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

21. 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

22. 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

23. 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

24. A common molecular signature of patients with sickle cell disease revealed by microarray meta-analysis and a genome-wide association study

Author: Sumir Panji, Julie Makani, Liberata Mwita, Cherif Ben Hamda, Kais Ghedira, Raphael Z. Sangeda, Alia Benkahla, Ayton Meintjes, Lamia Guizani-Tabbane, Siana Nkya, Nicola Mulder, Faculté des Sciences de Bizerte [Université de Carthage], Université de Carthage - University of Carthage, Laboratoire de Bioinformatique, biomathématiques, biostatistiques (BIMS) (LR11IPT09), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Tunis El Manar (UTM), Université de Tunis El Manar (UTM), Muhimbili University of Health and Allied Sciences, University of Cape Town, Laboratoire de Parasitologie Médicale, Biotechnologies et Biomolécules (LR11IPT06), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Research reported in this publication was supported by the National Institutes of Health Common Fund under grant number U41HG006941 (NM)., and The authors would like to thank Pr. Faisal Fadlelmola and Dr. Amel Ghouila the chair and co-chair of the H3ABioNet Research and Tool Development Working Group for the follow up of the present project.
Subjects: 0301 basic medicine, MESH: Gene Ontology, Candidate gene, Microarray, Microarrays, Physiology, MESH: Gene Expression Profiling, [SDV]Life Sciences [q-bio], Gene regulatory network, lcsh:Medicine, Gene Expression, Genome-wide association study, Biochemistry, MESH: Genotype, Mathematical and Statistical Techniques, Databases, Genetic, Medicine and Health Sciences, MESH: Computational Biology/methods, Data Mining, Gene Regulatory Networks, Post-Translational Modification, lcsh:Science, MESH: Databases, Genetic, MESH: Gene Regulatory Networks, Regulation of gene expression, MESH: Transcriptome, Multidisciplinary, MESH: Anemia, Sickle Cell/genetics, MESH: Polymorphism, Single Nucleotide, Genomics, MESH: Genome-Wide Association Study, 3. Good health, Body Fluids, Bioassays and Physiological Analysis, Blood, Physical Sciences, DNA microarray, Anatomy, Statistics (Mathematics), Research Article, Genotype, Computational biology, Heme, Anemia, Sickle Cell, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, DNA-binding proteins, Genetics, Genome-Wide Association Studies, SNP, Humans, Gene Regulation, Statistical Methods, Alleles, MESH: Humans, MESH: Alleles, MESH: Data Mining, Gene Expression Profiling, lcsh:R, Biology and Life Sciences, Computational Biology, Proteins, Human Genetics, Genome Analysis, Regulatory Proteins, Gene expression profiling, 030104 developmental biology, Gene Ontology, lcsh:Q, Transcriptome, Mathematics, Meta-Analysis, Transcription Factors, Genome-Wide Association Study
Abstract: International audience; A chronic inflammatory state to a large extent explains sickle cell disease (SCD) pathophysi-ology. Nonetheless, the principal dysregulated factors affecting this major pathway and their mechanisms of action still have to be fully identified and elucidated. Integrating gene expression and genome-wide association study (GWAS) data analysis represents a novel approach to refining the identification of key mediators and functions in complex diseases. Here, we performed gene expression meta-analysis of five independent publicly available microarray datasets related to homozygous SS patients with SCD to identify a consensus SCD transcriptomic profile. The meta-analysis conducted using the MetaDE R package based on combining p values (maxP approach) identified 335 differentially expressed genes (DEGs; 224 upregulated and 111 downregulated). Functional gene set enrichment revealed the importance of several metabolic pathways, of innate immune responses, erythrocyte development, and hemostasis pathways. Advanced analyses of GWAS data generated within the framework of this study by means of the atSNP R package and SIFT tool identified 60 regulatory single-nucleotide polymorphisms (rSNPs) occurring in the promoter of 20 DEGs and a deleterious SNP, affecting CAMKK2 protein function. This novel database of candidate genes, transcription factors, and rSNPs associated with SCD provides new markers that may help to identify new therapeutic targets.
Published: 2018

25. 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

26. 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

27. FOXE3 mutations: Genotype-phenotype correlations

Author: Plaisancié, Julie, Ragge, N.K., Dollfus, H., Kaplan, J., Lehalle, D., Francannet, C., Morin, G., Colineaux, H., Calvas, Patrick, Chassaing, Nicolas, 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 Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU 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 Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), and CARBILLET, Véronique
Subjects: MESH: Developmental Disabilities / physiopathology, MESH: Mutation, genetic structures, genotype-phenotype correlations, MESH: Eye Abnormalities / physiopathology, anophthalmia, MESH: Aphakia / genetics, MESH: Forkhead Transcription Factors / genetics, MESH: Genetic Predisposition to Disease, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Developmental Disabilities / genetics, MESH: Microphthalmos / physiopathology, MESH: Humans, MESH: Alleles, aphakia, MESH: Microphthalmos / genetics, MESH: Aphakia / physiopathology, eye diseases, MESH: Male, microphthalmia, cataract, MESH: Eye Abnormalities / genetics, eye development, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. Plasmodium vivax genetic diversity and heterozygosity in blood samples and resulting oocysts at the Thai–Myanmar border

Author: François Nosten, Richard Paul, Ingfar Soontarawirat, Charles J. Woodrow, Chiara Andolina, Nicholas P. J. Day, Mallika Imwong, Mahidol University [Bangkok], University of Oxford, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and This study had financial support from Mahidol University, the Royal Golden Jubilee Ph.D. program scholarship of the Thailand Research Fund (TRF), Franco-Thai Scholarship and the Mahidol-Oxford Tropical Medicine Research Unit supported by the Wellcome Trust of Great Britain.
Subjects: 0301 basic medicine, Genotyping Techniques, Plasmodium vivax, Myanmar, Genetic diversity, MESH: Genotype, Loss of heterozygosity, Oocyst, 0302 clinical medicine, MESH: Animals, MESH: Genetic Variation, Relapse, MESH: Heterozygote, Genetics, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, education.field_of_study, biology, MESH: Myanmar, Thailand, MESH: Plasmodium vivax, 3. Good health, Meiosis, Infectious Diseases, Microsatellite, Female, Inbreeding, MESH: Oocysts, Heterozygote, lcsh:Arctic medicine. Tropical medicine, Genotype, lcsh:RC955-962, 030231 tropical medicine, Population, MESH: DNA, Protozoan, MESH: Insect Vectors, lcsh:Infectious and parasitic diseases, MESH: Anopheles, 03 medical and health sciences, MESH: Genotyping Techniques, Anopheles, parasitic diseases, Malaria, Vivax, Animals, Humans, lcsh:RC109-216, Allele, MESH: Thailand, education, Alleles, MESH: Humans, Research, MESH: Alleles, fungi, Oocysts, Genetic Variation, MESH: Malaria, Vivax, DNA, Protozoan, biology.organism_classification, Insect Vectors, Minor allele frequency, MESH: Meiosis, 030104 developmental biology, Parasitology, MESH: Microsatellite Repeats, MESH: Female, Microsatellite Repeats
Abstract: Background Polyclonal blood-stage infections of Plasmodium vivax are frequent even in low transmission settings, allowing meiotic recombination between heterologous parasites. Empirical data on meiotic products are however lacking. This study examined microsatellites in oocysts derived by membrane feeding of mosquitoes from blood-stage P. vivax infections at the Thai–Myanmar border. Methods Blood samples from patients presenting with vivax malaria were fed to Anopheles cracens by membrane feeding and individual oocysts from midguts were obtained by dissection after 7 days. DNA was extracted from oocysts and parental blood samples and tested by microsatellite analysis. Results A focused study of eight microsatellite markers was undertaken for nine blood stage infections from 2013, for which derived oocysts were studied in six cases. One or more alleles were successfully amplified for 131 oocysts, revealing high levels of allelic diversity in both blood and oocyst stages. Based on standard criteria for defining minor alleles, there was evidence of clear deviation from random mating (inbreeding) with relatively few heterozygous oocysts compared to variance across the entire oocyst population (FIT = 0.89). The main explanation appeared to be natural compartmentalisation at mosquito (FSC = 0.27) and human stages (FCT = 0.68). One single human case produced a total of 431 successfully amplified loci (across 70 oocysts) that were homozygous and identical to parental alleles at all markers, indicating clonal infection and transmission. Heterozygous oocyst alleles were found at 15/176 (8.5%) successfully amplified loci in the other five cases. There was apparently reduced oocyst heterozygosity in individual oocysts compared to diversity within individual mosquitoes (FIS = 0.55), but this may simply reflect the difficulty of detecting minor alleles in oocysts, given the high rate of amplification failure. Inclusion of minor allele peaks (irrespective of height) when matching peaks were found in related blood or oocyst samples, added 11 minor alleles for 9 oocysts, increasing the number of heterozygous loci to 26/176 (14.8%; p = 0.096). Conclusion There was an apparently low level of heterozygous oocysts but this can be explained by a combination of factors: relatively low complexity of parental infection, natural compartmentalisation in humans and mosquitoes, and the methodological challenge of detecting minor alleles. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-2002-x) contains supplementary material, which is available to authorized users.
Published: 2017

34. Degeneration of serotonin neurons triggers spasticity in amyotrophic lateral sclerosis

Author: El Oussini, Hajer, Scekic-Zahirovic, Jelena, Vercruysse, Pauline, Marques, Christine, Dirrig-Grosch, Sylvie, Dieterlé, Stéphane, Picchiarelli, Gina, Sinniger, Jérôme, Rouaux, Caroline, Dupuis, Luc, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), University of Ulm (UUlm), and Dieterle, Stéphane
Subjects: MESH: Mutation, MESH: Mice, Transgenic, [SDV]Life Sciences [q-bio], Mice, Transgenic, MESH: Nerve Degeneration, Mice, [SCCO]Cognitive science, Superoxide Dismutase-1, Animals, MESH: Animals, MESH: Mice, Alleles, MESH: Amyotrophic Lateral Sclerosis, MESH: Superoxide Dismutase-1, MESH: Muscle Spasticity, MESH: Serotonergic Neurons, MESH: Alleles, Amyotrophic Lateral Sclerosis, [SCCO] Cognitive science, nervous system diseases, [SDV] Life Sciences [q-bio], Disease Models, Animal, Muscle Spasticity, Mutation, Nerve Degeneration, MESH: Disease Models, Animal, Serotonergic Neurons
Abstract: International audience; Objective: Spasticity occurs in a wide range of neurological diseases, including neurodegenerative diseases, after trauma, and after stroke, and is characterized by increased reflexes leading to muscle hypertonia. Spasticity is a painful symptom and can severely restrict everyday life, but might also participate in maintaining a low level of motor function in severely impaired patients. Constitutive activity of the serotonin receptors 5-HT2B/C is required for the development of spasticity after spinal cord injury and during amyotrophic lateral sclerosis (ALS). We sought here to provide direct evidence for a role of brainstem serotonin neurons in spasticity.Methods: SOD1(G37R) mice expressing a conditional allele of an ALS-linked SOD1 mutation were crossed with Tph2-Cre mice expressing Cre in serotonergic neurons. Measurement of long-lasting reflex using electromyography, behavioral follow-up, and histological techniques was used to characterize spasticity and motor phenotype.Results: Deleting mutant SOD1 expression selectively in brainstem serotonin neurons was sufficient to rescue loss of TPH2 immunoreactivity and largely preserve serotonin innervation of motor neurons in the spinal cord. Furthermore, this abrogated constitutive activity of 5-HT2B/C receptors and abolished spasticity in end-stage mice. Consistent with spasticity mitigating motor symptoms, selective deletion worsened motor function and accelerated the onset of paralysis.Interpretation: Degeneration of serotonin neurons is necessary to trigger spasticity through the 5-HT2B/C receptor. The wide range of drugs targeting the serotonergic system could be useful to treat spasticity in neurological diseases. Ann Neurol 2017;82:444-456.
Published: 2017

35. 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

36. 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

37. The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1

Author: Cornick, Jennifer E., Tastan Bishop, Özlem, Yalcin, Feyruz, Kiran, Anmol M., Kumwenda, Benjamin, Chaguza, Chrispin, Govindpershad, Shanil, Ousmane, Sani, Senghore, Madikay, du Plessis, Mignon, Pluschke, Gerd, Ebruke, Chinelo, McGee, Lesley, Sigaùque, Beutel, Collard, Jean-Marc, Bentley, Stephen D., Kadioglu, Aras, Antonio, Martin, von Gottberg, Anne, French, Neil, Klugman, Keith P., Heyderman, Robert S., Alderson, Mark, Everett, Dean B., PAGe consortium, Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), Liverpool School of Tropical Medicine (LSTM)-University of Liverpool-Wellcome Trust-University of Malawi, University of Liverpool, Rhodes University, Grahamstown, The Wellcome Trust Sanger Institute [Cambridge], National Institute for Communicable Diseases [Johannesburg] (NICD), University of the Witwatersrand [Johannesburg] (WITS), Centre de Recherche Médicale et Sanitaire (Niamey, Niger) (CERMES), Réseau International des Instituts Pasteur (RIIP), Medical Research Council Unit The Gambia (MRC), University of Warwick [Coventry], Swiss Tropical and Public Health Institute [Basel], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), London School of Hygiene and Tropical Medicine (LSHTM), Emory University [Atlanta, GA], PATH [Seattle], This work supported by the Bill and Melinda Gates Foundation (Grant No. OPP1023440), Wellcome Trust (Award No. 084679/Z/08/Z), National Research Foundation of South Africa (Grant No. 93690) and the NIH Common Fund Award (H3A Bionet) (Grant No. U41HG006941)., and A full list of PAGe members can be found at http://www.pagegenomes.org/page/consortium
Subjects: Models, Molecular, Vaccination Coverage, Antigenic diversity, MESH: Geography, MESH: Vaccines, Subunit, MESH: Amino Acid Sequence, MESH: Global Health, MESH: Africa, MESH: Virulence, Global Health, Structural diversity, Pneumococcal Vaccines, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Pneumococcal Infections, Variant, MESH: Bacterial Proteins, Geography, Virulence, MESH: Asia, Research Support, Non-U.S. Gov't, MESH: Vaccination Coverage, Protein modelling, Antigenic Variation, Europe, Infectious Diseases, Streptococcus pneumoniae, Vaccines, Subunit, Molecular Medicine, MESH: Antigenic Variation, PCV, MESH: Models, Molecular, MESH: Streptococcus pneumoniae, MESH: Pneumococcal Vaccines, Asia, Antigenic profiling, Pneumococcal disease, Serogroup, Article, Pneumococcal Infections, Bacterial Proteins, Research Support, N.I.H., Extramural, Immunology and Microbiology(all), Journal Article, Humans, Multi-valent, Amino Acid Sequence, Alleles, Antigens, Bacterial, MESH: Humans, MESH: Alleles, Public Health, Environmental and Occupational Health, MESH: Serogroup, MESH: South America, South America, veterinary(all), [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, MESH: Antigens, Bacterial
Abstract: International audience; Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (
Published: 2017

38. 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

39. Bayesian population structure analysis reveals presence of phylogeographically specific sublineages within previously ill-defined T group of Mycobacterium tuberculosis

Author: Qun Sun, Guihui Wu, Chao Zheng, Yann Reynaud, Nalin Rastogi, Institut Pasteur de la Guadeloupe, Réseau International des Instituts Pasteur (RIIP), Sichuan University [Chengdu] (SCU), Public Health Clinical Center of Chengdu, and This work was supported by the European Regional Development Fund and European Social Fund (ERDF-ESF) under the scheme 'Programme Opérationnel FEDER-FSE Guadeloupe Conseil Régional 2014–2020' (Grant number pending). Yann Reynaud was awarded a Calmette and Yersinpostdoctoral fellowship by the Institut Pasteur International Network. Chao Zheng as financially supported by China Scholarship Council (CSC,File NO.201506240129) under a co-training program for the fulfillment of his PhD research program between College of Life Sciences, SichuanUniversity , Chengdu, China, and Tuberculosis and Mycobacteria Unit, Institut Pasteur de la Guadeloupe.
Subjects: Evolutionary Genetics, 0301 basic medicine, MESH: Mycobacterium tuberculosis, Lineage (evolution), Gene Dosage, lcsh:Medicine, Minisatellite Repeats, Plant Science, Plant Roots, MESH: Gene Dosage, Geographical Locations, MESH: Genotype, MESH: Phylogeny, lcsh:Science, Phylogeny, MESH: Evolution, Molecular, Data Management, Multidisciplinary, Geography, Phylogenetic tree, Plant Anatomy, 3. Good health, Actinobacteria, Phylogenetics, Phylogeography, MESH: Multilocus Sequence Typing, Biogeography, MESH: Phylogeography, Genetic structure, Research Article, Computer and Information Sciences, China, Genotyping, Asia, Genotype, MESH: Bayes Theorem, 030106 microbiology, Biology, Research and Analysis Methods, Evolution, Molecular, Computer Software, Mycobacterium tuberculosis, 03 medical and health sciences, Genetics, Evolutionary Systematics, Molecular Biology Techniques, Molecular Biology, Alleles, Taxonomy, Whole genome sequencing, Evolutionary Biology, Bacteria, Population Biology, MESH: Alleles, Ecology and Environmental Sciences, lcsh:R, Organisms, Biology and Life Sciences, Bayes Theorem, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Root Structure, 030104 developmental biology, Genetic marker, Evolutionary biology, People and Places, MESH: Minisatellite Repeats, Earth Sciences, lcsh:Q, Population Genetics, Multilocus Sequence Typing
Abstract: International audience; Mycobacterium tuberculosis genetic structure, and evolutionary history have been studied for years by several genotyping approaches, but delineation of a few sublineages remains controversial and needs better characterization. This is particularly the case of T group within lineage 4 (L4) which was first described using spoligotyping to pool together a number of strains with ill-defined signatures. Although T strains were not traditionally considered as a real phylogenetic group, they did contain a few phylogenetically meaningful sublineages as shown using SNPs. We therefore decided to investigate if this observation could be corroborated using other robust genetic markers. We consequently made a first assessment of genetic structure using 24-loci MIRU-VNTRs data extracted from the SITVIT2 database (n = 607 clinical isolates collected in Russia, Albania, Turkey, Iraq, Brazil and China). Combining Minimum Spanning Trees and Bayesian population structure analyses (using STRUCTURE and TESS softwares), we distinctly identified eight tentative phylogenetic groups (T1-T8) with a remarkable correlation with geographical origin. We further compared the present structure observed with other L4 sublineages (n = 416 clinical isolates belonging to LAM, Haarlem, X, S sublineages), and showed that 5 out of 8 T groups seemed phylogeographi-cally well-defined as opposed to the remaining 3 groups that partially mixed with other L4 isolates. These results provide with novel evidence about phylogeographically specificity of a proportion of ill-defined T group of M. tuberculosis. The genetic structure observed will now be further validated on an enlarged worldwide dataset using Whole Genome Sequenc-ing (WGS).
Published: 2017

40. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator

Author: Charlotte Passemar, Alexandre Pawlik, Wladimir Malaga, Flavie Moreau, Mamadou Daffé, Carlos Martin, Roland Brosch, Christophe Guilhot, Catherine Astarie-Dequeker, Françoise Laval, Jesús Gonzalo-Asensio, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported in part by the Juan de la Cierva Programme JCI-2009-03799 from the Spanish Ministry of Science and Innovation (to J.G.-A.), the Centre National de la Recherche Scientifique, the Fondation pour la Recherche Médicale ('Equipe FRM' DEQ20090515399 and DEQ20130326471), the European Union 7th Framework Programme (Contracts NEWTBVAC 241745, MM4TB 260872, and FEDER/POCTEFA/REFBIO EFA237/11), the Spanish Ministry of Economy and Competitiveness (Contracts BIO2011-23555 and FIS12/1970), and the Région Midi-Pyrénées (CPER 2007-2013) for the scientific project and for the ASB3 animal facility., We thank Dr. Geanncarlo Lugo-Villarino and Dr. Stephen V. Gordon for critical reading of the manuscript. We thank the members of the Genotoul platforms TRI and ANEXPLO (Institut de Pharmacologie et de Biologie Structurale) for epifluorescence microscopy imaging and for animal experiments, respectively, and Dr. Marie-Agnès Dillies and Dr. Jean-Yves Coppée from the Transcriptome Platform PF2 at the Institut Pasteur for advice., European Project: 241745,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,NEWTBVAC(2010), European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: adaptation, MESH: Animals, MESH: Phylogeny, Conserved Sequence, Phylogeny, Genetics, Mycobacterium bovis, Multidisciplinary, Virulence, Genetic transfer, Biological Sciences, Biological Evolution, 3. Good health, MESH: Cattle, Host-Pathogen Interactions, MESH: Mycobacterium tuberculosis / genetics, MESH: Conserved Sequence / genetics, Locus (genetics), MESH: Mycobacterium tuberculosis / pathogenicity, Biology, Polymorphism, Single Nucleotide, MESH: Biological Evolution, Mycobacterium, Microbiology, Mycobacterium tuberculosis, Bacterial Proteins, evolution, MESH: Virulence / genetics, Animals, Humans, Tuberculosis, Secretion, MESH: Mycobacterium bovis / pathogenicity, MESH: Bacterial Proteins / metabolism, Alleles, Antigens, Bacterial, MESH: Humans, MESH: Alleles, MESH: Host-Pathogen Interactions, zoonosis, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Mycobacterium / genetics, Mutagenesis, Insertional, Regulon, MESH: Mutagenesis, Insertional, MESH: Bacterial Proteins / genetics, MESH: Gene Deletion, MESH: Mutation / genetics, MESH: Mycobacterium bovis / genetics, Mutation, Cattle, MESH: Polymorphism, Single Nucleotide / genetics, MESH: Tuberculosis / microbiology, MESH: Tuberculosis / genetics, Mycobacterium africanum, MESH: Antigens, Bacterial, Gene Deletion
Abstract: International audience; Although the bovine tuberculosis (TB) agent, Mycobacterium bovis, may infect humans and cause disease, long-term epidemiological data indicate that humans represent a spill-over host in which infection with M. bovis is not self-maintaining. Indeed, human-to-human transmission of M. bovis strains and other members of the animal lineage of the tubercle bacilli is very rare. Here, we report on three mutations affecting the two-component virulence regulation system PhoP/PhoR (PhoPR) in M. bovis and in the closely linked Mycobacterium africanum lineage 6 (L6) that likely account for this discrepancy. Genetic transfer of these mutations into the human TB agent, Mycobacterium tuberculosis, resulted in down-regulation of the PhoP regulon, with loss of biologically active lipids, reduced secretion of the 6-kDa early antigenic target (ESAT-6), and lower virulence. Remarkably, the deleterious effects of the phoPR mutations were partly compensated by a deletion, specific to the animal-adapted and M. africanum L6 lineages, that restores ESAT-6 secretion by a PhoPR-independent mechanism. Similarly, we also observed that insertion of an IS6110 element upstream of the phoPR locus may completely revert the phoPR-bovis-associated fitness loss, which is the case for an exceptional M. bovis human outbreak strain from Spain. Our findings ultimately explain the long-term epidemiological data, suggesting that M. bovis and related phoPR-mutated strains pose a lower risk for progression to overt human TB, with major impact on the evolutionary history of TB.
Published: 2014

41. Gene-Flow in a Mosaic Hybrid Zone: Is Local Introgression Adaptive?

Author: Nicolas Bierne, John J. Welch, Camille Roux, Christelle Fraïsse, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Department of Genetics [Cambridge], University of Cambridge [UK] (CAM), Department of Ecology and Evolution [Lausanne], and Université de Lausanne (UNIL)
Subjects: MESH: Geography, MESH: Base Sequence, Polymerase Chain Reaction, Gene flow, MESH: Animals, Inbreeding, MESH: Models, Genetic, maximum likelihood, MESH: Phylogeny, Phylogeny, Genetics, Likelihood Functions, Genome, Geography, Mosaicism, outlier loci, Reproductive isolation, Adaptation, Physiological, Europe, MESH: Mosaicism, Approximate Bayesian computation, Algorithms, Gene Flow, MESH: Mytilus, Introgression, MESH: Algorithms, Locus (genetics), Investigations, Biology, MESH: Genetic Loci, Chromosomes, approximate Bayesian computation, Hybrid zone, Species Specificity, MESH: Inbreeding, MESH: Polymorphism, Genetic, MESH: Species Specificity, Animals, MESH: Genome, Allele, MESH: Gene Flow, Alleles, Mytilus, Polymorphism, Genetic, Base Sequence, Models, Genetic, MESH: Alleles, soft sweep, MESH: Polymerase Chain Reaction, MESH: Adaptation, Physiological, MESH: Hybridization, Genetic, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Genetic Loci, Hybridization, Genetic, MESH: Likelihood Functions, MESH: Chromosomes, MESH: Europe
Abstract: Genome-wide scans of genetic differentiation between hybridizing taxa can identify genome regions with unusual rates of introgression. Regions of high differentiation might represent barriers to gene flow, while regions of low differentiation might indicate adaptive introgression—the spread of selectively beneficial alleles between reproductively isolated genetic backgrounds. Here we conduct a scan for unusual patterns of differentiation in a mosaic hybrid zone between two mussel species, Mytilus edulis and M. galloprovincialis. One outlying locus, mac-1, showed a characteristic footprint of local introgression, with abnormally high frequency of edulis-derived alleles in a patch of M. galloprovincialis enclosed within the mosaic zone, but low frequencies outside of the zone. Further analysis of DNA sequences showed that almost all of the edulis allelic diversity had introgressed into the M. galloprovincialis background in this patch. We then used a variety of approaches to test the hypothesis that there had been adaptive introgression at mac-1. Simulations and model fitting with maximum-likelihood and approximate Bayesian computation approaches suggested that adaptive introgression could generate a “soft sweep,” which was qualitatively consistent with our data. Although the migration rate required was high, it was compatible with the functioning of an effective barrier to gene flow as revealed by demographic inferences. As such, adaptive introgression could explain both the reduced intraspecific differentiation around mac-1 and the high diversity of introgressed alleles, although a localized change in barrier strength may also be invoked. Together, our results emphasize the need to account for the complex history of secondary contacts in interpreting outlier loci.
Published: 2014

42. 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

43. 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

44. 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

45. Higher-Order Looping and Nuclear Organization of Tcra Facilitate Targeted RAG Cleavage and Regulated Rearrangement in Recombination Centers

Author: David G. Schatz, Iannis Aifantis, Panagiotis Ntziachristos, Mariann Micsinai, Joy M. H. Wang, Ludovic Deriano, Yuval Kluger, Jeffrey A. Jeddeloh, Elphège P. Nora, Matthew Rodesch, Julie Chaumeil, Yanhong Ji, Jane A. Skok, New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Développement lymphocytaire et Oncogénèse, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Roche NimbleGen Inc., Yale Cancer Center, Yale School of Medicine [New Haven, Connecticut] (YSM), Yale University [New Haven], Howard Hughes Medical Institute (HHMI), This work is supported by the National Institute ofHealth: R01GM086852 (to J.A.S.), R37AI32524 (to D.G.S.), RO1CA133379,RO1CA105129, RO1CA149655, and RO1GM088847 (to I.A.). J.A.S. is aLeukemia & Lymphoma Society (LLS) scholar. J.C. is an Irvington Institute Fellow of the Cancer Research Institute. M.M. was supported by an NSFIGERT 0333389. L.D. was an LLS Fellow. E.P.N. was supported by the FrenchMinistry of Research and the Association pour la Recherche sur le Cancer(France). I.A. is also supported by the Leukemia & Lymphoma Society (TRPgrant), The V Foundation for Cancer Research, and the Dana Foundation.D.G.S. is an Investigator, and I.A. is an Early Career Scientist of the HowardHughes Medical Institute. The authors from Roche NimbleGen, Inc. (M.J.R.and J.A.J.) recognize a competing interest in this publication as employeesof the company., Lassailly-Bondaz, Anne, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Yale University School of Medicine
Subjects: Genome instability, MESH: V(D)J Recombination, Ataxia Telangiectasia Mutated Proteins, Inbred C57BL, MESH: Mice, Knockout, Tumor Suppressor Proteins/metabolism, Mice, 0302 clinical medicine, Transcription (biology), Receptors, Recombinase, Medicine and Health Sciences, MESH: Animals, MESH: Ataxia Telangiectasia Mutated Proteins, lcsh:QH301-705.5, DNA-Binding Proteins/genetics/*metabolism, Genetics, MESH: Histones, 0303 health sciences, MESH: Mice, Inbred CBA, MESH: Receptors, Antigen, T-Cell, alpha-beta, biology, MESH: Genomic Instability, V(D)J recombination, Protein-Serine-Threonine Kinases/metabolism, Chromatin, alpha-beta/genetics/*metabolism, Histone, Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cell Nucleus, [SDV.IMM] Life Sciences [q-bio]/Immunology, Knockout, Cleavage (embryo), DNA-binding protein, MESH: Genetic Loci, General Biochemistry, Genetics and Molecular Biology, Genomic Instability, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH: Mice, Inbred C57BL, MESH: Homeodomain Proteins, Homeodomain Proteins/genetics/*metabolism, Animals, MESH: Tumor Suppressor Proteins, MESH: Mice, Alleles, 030304 developmental biology, MESH: DNA Damage, Histones/genetics, Cell Cycle Proteins/metabolism, MESH: Alleles, Inbred CBA, Biology and Life Sciences, T-Cell, lcsh:Biology (General), Genetic Loci, Cell Nucleus/metabolism, biology.protein, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, V(D)J Recombination, DNA Damage
Abstract: International audience; V(D)J recombination is essential for generating a diverse array of B and T cell receptors that can recognize and combat foreign antigens. As with any recombination event, tight control is essential to prevent the occurrence of genetic anomalies that drive cellular transformation. One important aspect of regulation is directed targeting of the RAG recombinase. Indeed, RAG accumulates at the 3' end of individual antigen receptor loci poised for rearrangement; however, it is not known whether focal binding is involved in regulating cleavage, and what mechanisms lead to enrichment of RAG in this region. Here, we show that monoallelic looping out of the 3' end of the T cell receptor α (Tcra) locus, coupled with transcription and increased chromatin/nuclear accessibility, is linked to focal RAG binding and ATM-mediated regulation of monoallelic cleavage on looped-out 3' regions. Our data identify higher-order loop formation as a key determinant of directed RAG targeting and the maintenance of genome stability.
Published: 2013
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46. Spatial pattern of genetic diversity and selection in the MHC class II DRB of three Neotropical bat species

Author: Benoit de Thoisy, Brigitte Crouau-Roy, Vincent Lacoste, Arielle Salmier, Anne Lavergne, Laboratoire des Interactions Virus-Hôtes [Cayenne, Guyane Française], Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), A. Salmier was supported by a grant from European funds (PO FSE 2007-2013) and 'Investissement d’Avenir' managed by Agence Nationale de la Recherche (CEBA, Ref. ANR-10- LABEX-25-01). This study was conducted within the CAROLIA program supported by European funds (ERDF/FEDER) and assistance from Région Guyane and Direction Régionale pour la Recherche et la Technologie. It also received a European Commission 'REGPOT-CT-2011-285837- STRonGer' grant within the FP7 and 'Investissement d’Avenir' grants managed by the Agence Nationale de la Recherche (CEBA, Ref. ANR-10- LABEX-25-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., We are grateful to François Catzeflis and Marguerite Delaval for useful discussions on the biology, ecology and dynamics of bats. All field volunteers and owners and/or managers of capture sites are warmly acknowledged for their assistance in captures., ANR-10-LABX-0025,CEBA,CEnter of the study of Biodiversity in Amazonia(2010), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: 0106 biological sciences, 0301 basic medicine, Molossus molossus, 01 natural sciences, Chiroptera, MESH: Gene Conversion, MESH: Animals, MESH: Histocompatibility Antigens Class II/genetics, MESH: Phylogeny, Phylogeny, Carollia perspicillata, education.field_of_study, MESH: Genetic Variation, biology, Phylogenetic tree, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], MESH: Genes, MHC Class II, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Sympatric speciation, Host-Pathogen Interactions, Research Article, DRB polymorphism, Genes, MHC Class II, Population, MESH: Host-Pathogen Interactions/genetics, Gene Conversion, MESH: Selection, Genetic, Zoology, Desmodus rotundus, 010603 evolutionary biology, MESH: Gastrointestinal Microbiome, Evolution, Molecular, 03 medical and health sciences, MESH: Histocompatibility Antigens Class II/chemistry, MESH: Chiroptera/genetics, MESH: Evolution, Molecular, MESH: Polymorphism, Genetic, Genetic variation, Animals, Selection, Genetic, education, Selection, Alleles, Ecology, Evolution, Behavior and Systematics, Genetic diversity, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Polymorphism, Genetic, MESH: Alleles, Histocompatibility Antigens Class II, Genetic Variation, 15. Life on land, biology.organism_classification, Gastrointestinal Microbiome, 030104 developmental biology, MHC
Abstract: Background Although bats are natural reservoirs of many pathogens, few studies have been conducted on the genetic variation and detection of selection in major histocompatibility complex (MHC) genes. These genes are critical for resistance and susceptibility to diseases, and host–pathogen interactions are major determinants of their extensive polymorphism. Here we examined spatial patterns of diversity of the expressed MHC class II DRB gene of three sympatric Neotropical bats, Carollia perspicillata and Desmodus rotundus (Phyllostomidae), and Molossus molossus (Molossidae), all of which use the same environments (e.g., forests, edge habitats, urban areas). Comparison with neutral marker (mtDNA D-loop) diversity was performed at the same time. Results Twenty-three DRB alleles were identified in 19 C. perspicillata, 30 alleles in 35 D. rotundus and 20 alleles in 28 M. molossus. The occurrence of multiple DRB loci was found for the two Phyllostomidae species. The DRB polymorphism was high in all sampling sites and different signatures of positive selection were detected depending on the environment. The patterns of DRB diversity were similar to those of neutral markers for C. perspicillata and M. molossus. In contrast, these patterns were different for D. rotundus for which a geographical structure was highlighted. A heterozygote advantage was also identified for this species. No recombination or gene conversion event was found and phylogenetic relationships showed a trans-species mode of evolution in the Phyllostomids. Conclusions This study of MHC diversity demonstrated the strength of the environment and contrasting pathogen pressures in shaping DRB diversity. Differences between positively selected sites identified in bat species highlighted the potential role of gut microbiota in shaping immune responses. Furthermore, multiple geographic origins and/or population admixtures observed in C. perspicillata and M. molossus populations acted as an additional force in shaping DRB diversity. In contrast, DRB diversity of D. rotundus was shaped by environment rather than demographic history. Electronic supplementary material The online version of this article (doi:10.1186/s12862-016-0802-1) contains supplementary material, which is available to authorized users.
Published: 2016

47. Otopalatodigital spectrum disorders: Refinement of the phenotypic and mutational spectrum

Author: Moutton, Sébastien, Fergelot, Patricia, Naudion, Sophie, Cordier, Marie-Pierre, Solé, Guilhem, Guerineau, Elodie, Hubert, Christophe, Rooryck, Caroline, Vuillaume, Marie-Laure, Houcinat, Nada, Deforges, Julie, Bouron, Julie, Devès, Sylvie, Le Merrer, Martine, David, Albert, Geneviève, David, Giuliano, Fabienne, Journel, Hubert, Megarbane, André, Faivre, Laurence, Chassaing, Nicolas, Francannet, Christine, Sarrazin, Elisabeth, Stattin, Eva-Lena, Vigneron, Jacqueline, Leclair, Danielle, Abadie, Caroline, Sarda, Pierre, Baumann, Clarisse, Delrue, Marie-Ange, Arveiler, Benoit, Lacombe, Didier, Goizet, Cyril, Coupry, Isabelle, 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), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Department of Neurology [Bordeaux], CHU Bordeaux [Bordeaux], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Osteochondrodysplasias / genetics, MESH: Sequence Analysis, DNA, MESH: Hand Deformities, Congenital / diagnosis, MESH: Humans, MESH: Hand Deformities, Congenital / genetics, MESH: Pedigree, MESH: Alleles, MESH: Phenotype, MESH: Amino Acid Substitution, MESH: Craniofacial Abnormalities / genetics, MESH: Male, MESH: Craniofacial Abnormalities / diagnosis, MESH: Facies, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Mutation, MESH: Osteochondrodysplasias / diagnosis, MESH: Exons, MESH: Filamins / genetics, MESH: Genetic Association Studies, 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: 2016

48. Population-associated differences between the phase variable LPS biosynthetic genes of Helicobacter pylori

Author: Salaün, Laurence, Saunders, Nigel J, Bacterial Pathogenesis and Functional Genomics Group, Sir William Dunn School of Pathology [Oxford], Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris]
Subjects: DNA, Bacterial, Lipopolysaccharides, MESH: Molecular Sequence Data, Base Sequence, Helicobacter pylori, MESH: Alleles, Molecular Sequence Data, lcsh:QR1-502, Genetic Variation, MESH: Base Sequence, MESH: DNA, Bacterial, lcsh:Microbiology, MESH: Variation (Genetics), Genes, Bacterial, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pathology, MESH: Helicobacter pylori, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Genes, Bacterial, MESH: Lipopolysaccharides, Alleles, Research Article
Abstract: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited - © 2006 Salaün and Saunders; licensee BioMed Central Ltd. Background: Population structures are normally determined using genes under minimal functional selection. In this study we have assessed genes that are not always essential, show differences in alleles between strains, and are involved in the directly host-selectable phenotype of LPS biosynthesis. Results: Eight complete LPS biosynthesis genes, seven of which are associated with phase variation in some or all strains of Helicobacter pylori, have been sequenced and their divergence analyzed. The differences observed indicate that recombination within these genes largely reflects exchange between strains within the population lineages previously determined on the basis of MLST using housekeeping genes. This indicates that the differences that are used for MLST are likely to broadly associate with genes under functional selection, and differences in strain behaviour. However, instances of exchange between the subpopulations were identified, including the hpAfrica2 subpopulation. Further, there were other differences in gene complements and the chromosomal location of genes indicative of greater diversity within the population than is revealed by the available genome sequences and comparative genome hybridization studies. Conclusion: These results indicate that the described population structure based upon MLST is broadly a good basis for studying the biology of H. pylori, but that individual alleles may not follow these associations. As a consequence, when working in unsequenced strains, it is necessary to carefully check the presence, sequence, and distribution of any individual gene of interest. This work is supported by a Wellcome Trust Advanced Fellowship.
Published: 2016

49. 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

50. 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

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