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

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Item Type:Article
Title:A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans
Creators Name:Vona, B. and Mazaheri, N. and Lin, S.J. and Dunbar, L.A. and Maroofian, R. and Azaiez, H. and Booth, K.T. and Vitry, S. and Rad, A. and Rüschendorf, F. and Varshney, P. and Fowler, B. and Beetz, C. and Alagramam, K.N. and Murphy, D. and Shariati, G. and Sedaghat, A. and Houlden, H. and Petree, C. and VijayKumar, S. and Smith, R.J.H. and Haaf, T. and El-Amraoui, A. and Bowl, M.R. and Varshney, G.K. and Galehdari, H.
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.
Keywords:Alleles, Amino Acid Substitution, Base Sequence, Chromosome Mapping, Consanguinity, Gene Expression, Inner Auditory Hair Cells, Membrane Proteins, Pair 4 Human Chromosomes, Pedigree, Point Mutation, Recessive Genes, Sensorineural Hearing Loss, Whole Exome Sequencing, Animals, Mice, Zebrafish
Source:Human Genetics
Page Range:915-931
Date:June 2021
Official Publication:https://doi.org/10.1007/s00439-020-02254-z
PubMed:View item in PubMed

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