Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis
| Autor: | Christian Renard, Christine Petit, Yosra Bouyacoub, Sedigheh Delmaghani, Magali Niasme-Grare, Nicolas Michalski, Hung Thai-Van, Olivier Deguine, Anne Aubois, Arnaud Deveze, Jean-Pierre Lavieille, Valérie Franco-Vidal, Anne-Laure Roudevitch-Pujol, Amrit Singh-Estivalet, Arnaud Coez, Vincent Michel, Christophe Vincent, Hugues Aschard, Claire Thibult-Apt, Amel Bahloul, Sophie Boucher, E. Ionescu, Bernard Fraysse, Fabienne Wong Jun Tai, Fabrice Giraudet, Vincent Darrouzet, Typhaine Dupont, Nicolas Wolff, Didier Bouccara, Lionel Collet, Crystel Bonnet, Gaelle M. Lefèvre, Jean-Louis Kemeny, Andrea Lelli, Eric Bizaguet, Paul Avan |
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| Přispěvatelé: | Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ED 515 - Complexité du vivant, Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Récepteurs Canaux - Channel Receptors, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Université Clermont Auvergne (UCA), Hôpital Nord [CHU - APHM], Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Hôpital Roger Salengro [Lille], Laboratoire d’Audiologie Renard, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de correction auditive Eric Bizaguet, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by a grant from Fondation pour l’Audition (to C.P.), LabEx Lifesenses Grant ANR-10-LABX-65, and Light4deaf Grant ANR-15-RHUS-0001., We thank the patients for participating in this study and Céline Trébeau for technical assistance. S.B. received funding from the University of Angers (Medical School), the University Hospital of Angers, and the Collège Français d’oto-rhino-laryngologistes., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Collège de France - Chaire Génétique et physiologie cellulaire, Bonnet, Crystel, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Presbycusis [SDV.GEN] Life Sciences [q-bio]/Genetics Deafness Cohort Studies Mice 0302 clinical medicine MESH: Presbycusis MESH: Animals Age of Onset MESH: Cohort Studies Genes Dominant Early onset MESH: Heterozygote Genetics Multidisciplinary monogenic disorder Age Factors Biological Sciences Phenotype MESH: Case-Control Studies Mitochondria 3. Good health age-related hearing loss symbols MESH: Membrane Proteins medicine.symptom Heterozygote MESH: Mutation Hearing loss MESH: Mitochondria MESH: Age of Onset MESH: Deafness Biology 03 medical and health sciences symbols.namesake MESH: Whole Exome Sequencing Exome Sequencing medicine Animals Humans Allele frequency Gene ultrarare variants MESH: Mice MESH: Age Factors [SDV.GEN]Life Sciences [q-bio]/Genetics MESH: Humans Membrane Proteins Tmc1 medicine.disease Comorbidity MicroRNAs 030104 developmental biology Case-Control Studies Mutation Mendelian inheritance MESH: Genes Dominant presbycusis MESH: MicroRNAs 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2020, 117 (49), pp.31278-31289. ⟨10.1073/pnas.2010782117⟩ Proceedings of the National Academy of Sciences of the United States of America, 2020, 117 (49), pp.31278-31289. ⟨10.1073/pnas.2010782117⟩ Proc Natl Acad Sci U S A |
| ISSN: | 0027-8424 1091-6490 |
| Popis: | International audience; Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls ( P = 0.001); half were previously unknown (AF < 0.000002). MYO6 , MYO7A , PTPRQ , and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1 N321I/+ mice, carrying the TMC1 :p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy. |
| Databáze: | OpenAIRE |
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