A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

Hum Genet. 2021 Jun;140(6):915-931. doi: 10.1007/s00439-020-02254-z.

Barbara Vona ¹ ², Neda Mazaheri ^# ³, Sheng-Jia Lin ^# ⁴, Lucy A Dunbar ^# ⁵, Reza Maroofian ⁶, Hela Azaiez ⁷, Kevin T Booth ⁷ ⁸, Sandrine Vitry ⁹, Aboulfazl Rad ¹⁰, Franz Rüschendorf ¹¹, Pratishtha Varshney ⁴, Ben Fowler ¹², Christian Beetz ¹³, Kumar N Alagramam ¹⁴ ¹⁵ ¹⁶, David Murphy ⁶, Gholamreza Shariati ¹⁷ ¹⁸, Alireza Sedaghat ¹⁹, Henry Houlden ⁶, Cassidy Petree ⁴, Shruthi VijayKumar ⁴, Richard J H Smith ⁷, Thomas Haaf ²⁰, Aziz El-Amraoui ⁹, Michael R Bowl ²¹ ²², Gaurav K Varshney ⁴, Hamid Galehdari ³

Affiliations

1 Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany. [email protected].
2 Department of Otolaryngology-Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, Germany. [email protected].
3 Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
4 Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
5 Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK.
6 Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
7 Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology and Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
8 Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
9 Unit Progressive Sensory Disorders, Pathophysiology and Therapy Institut Pasteur, Institut de L'Audition, INSERM-UMRS1120, Sorbonne Université, 63 rue de Charenton, 75012, Paris, France.
10 Department of Otolaryngology-Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, Germany.
11 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
12 Imaging & Histology Core, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
13 Centogene AG, Rostock, Germany.
14 Department of Otolaryngology, School of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.
15 Department of Neurosciences, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.
16 Department of Genetics and Genomic Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
17 Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz, Iran.
18 Narges Medical Genetics and Prenatal Diagnostics Laboratory, East Mihan Ave, Kianpars, Ahvaz, Iran.
19 Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
20 Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
21 Mammalian Genetics Unit, MRC Harwell Institute, Harwell Campus, Didcot, OX11 0RD, UK. [email protected].
22 UCL Ear Institute, University College London, 332 Gray's Inn Road, London, WC1X 8EE, UK. [email protected].
# Contributed equally.

PMID: 33496845 DOI: 10.1007/s00439-020-02254-z

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.

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