Journal article
A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans
Human genetics, Vol.140(6), pp.915-931
06/2021
DOI: 10.1007/s00439-020-02254-z
PMCID: PMC8099798
PMID: 33496845
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.
Details
- Title: Subtitle
- A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans
- Creators
- Barbara Vona - University of TübingenNeda Mazaheri - Shahid Chamran University of AhvazSheng-Jia Lin - Oklahoma Medical Research FoundationLucy A Dunbar - Mary Lyon Centre at MRC HarwellReza Maroofian - UCL Institute of NeurologyHela Azaiez - University of IowaKevin T Booth - Harvard UniversitySandrine Vitry - Institut PasteurAboulfazl Rad - University of TübingenFranz Rüschendorf - Max Delbrück CenterPratishtha Varshney - Oklahoma Medical Research FoundationBen Fowler - Oklahoma Medical Research FoundationChristian Beetz - Centogene AG, Rostock, Germany.Kumar N Alagramam - Case Western Reserve UniversityDavid Murphy - UCL Institute of NeurologyGholamreza Shariati - Ahvaz Jundishapur University of Medical SciencesAlireza Sedaghat - Ahvaz Jundishapur University of Medical SciencesHenry Houlden - UCL Institute of NeurologyCassidy Petree - Oklahoma Medical Research FoundationShruthi VijayKumar - Oklahoma Medical Research FoundationRichard J H Smith - Roy J. and Lucille A. Carver College of MedicineThomas Haaf - University of WürzburgAziz El-Amraoui - Institut PasteurMichael R Bowl - University College LondonGaurav K Varshney - Oklahoma Medical Research FoundationHamid Galehdari - Shahid Chamran University of Ahvaz
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.140(6), pp.915-931
- DOI
- 10.1007/s00439-020-02254-z
- PMID
- 33496845
- PMCID
- PMC8099798
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Grant note
- DC002842 / NIDCD NIH HHS ANR-15-RHUS-0001 / ANR light4deaf GM007748 / NIH HHS DC012049 / NIDCD NIH HHS 1774724 / Medical Research Council 2545-1-0 / Medizinischen Fakultät, Eberhard Karls Universität Tübingen MC_UP_1503/2 / Medical Research Council ANR-17-CE16-0017 / HearInNoise GM103636 (Project 3) / NIH HHS P20 GM103636 / NIGMS NIH HHS
- Language
- English
- Date published
- 06/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256838802771
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