1. 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