Vona, B;
Mazaheri, N;
Lin, S-J;
Dunbar, LA;
Maroofian, R;
Azaiez, H;
Booth, KT;
... Galehdari, H; + view all
(2021)
A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.
Human Genetics
10.1007/s00439-020-02254-z.
(In press).
Preview |
Text
Bowl_Vona2021_Article_ABiallelicVariantInCLRN2Causes.pdf - Published Version Download (7MB) | Preview |
Abstract
Deafness, the most frequent sensory defcit 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 identifed 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 zebrafsh and mouse models defcient for clarin 2 further confrm 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 fndings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
Type: | Article |
---|---|
Title: | A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans |
Location: | Germany |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1007/s00439-020-02254-z |
Publisher version: | https://doi.org/10.1007/s00439-020-02254-z |
Language: | English |
Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
URI: | https://discovery.ucl.ac.uk/id/eprint/10120232 |
Archive Staff Only
View Item |