Year: 2021
Type: article
Study design: Observational Study
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.
Source: Human Genetics
Authors: Barbara Vona, Neda Mazaheri, Sheng-Jia Lin, Lucy A. Dunbar, Reza Maroofian, Hela Azaiez, Kevin T. Booth, Sandrine Vitry, Aboulfazl Rad, Franz Rüschendorf, Pratishtha Varshney, Ben Fowler, Christian Beetz, Kumar N. Alagramam, David Murphy, Gholamreza Shariati, Alireza Sedaghat, Henry Houlden, Cassidy Petree, Shruthi VijayKumar, Richard J. H. Smith, Thomas Haaf, Aziz El-Amraoui, Michael R. Bowl, Gaurav K. Varshney, Hamid Galehdari
Institutions: University of Würzburg, University of Tübingen, Shahid Chamran University of Ahvaz, Oklahoma Medical Research Foundation, Mary Lyon Centre at MRC Harwell, UCL Queen Square Institute of Neurology, University College London, University of Iowa, Harvard University, Inserm, Institut Pasteur, Sorbonne Université, Institut de l'Audition, Max Delbrück Center, Centogene (Germany), University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, Case Western Reserve University, Ahvaz Jundishapur University of Medical Sciences
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: Presbyterian Health Foundation, Agence Nationale de la Recherche, Eberhard Karls Universität Tübingen, Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg, Julius-Maximilians-Universität Würzburg, National Institutes of Health, Medical Research Council, Medizinischen Fakultät, Eberhard Karls Universität Tübingen, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences
Awards: G1802016, LATE ONSET HEARING IMPAIRMENT: FROM DISEASE MECHANISMS TO THERAPY, G4950536974, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER, G5638354291, G6080759696, G6127496693, Non-Syndromic Hearing Loss A Collaborative Study, G6803667113, Expanding Excellence in Developmental Biology in Oklahoma, G7479502624, G9000252101, G9000301793, Optimizing Genetic Testing for Deafness for Clinical Diagnostics, Training Grant in Genetics
OpenAlex ID: W3125732001