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A novel nonsense mutation c.1121G>A (p.Trp374*) in the CLIC5 gene is the main cause of the juvenile autosomal recessive form of deafness (DFNB103) in the Arctic regions of Yakutia

Abstract

The most common cause of non-syndromic hearing loss in various populations of the world is the mutations in the GJB2 gene. Previously it was shown that the pathogenic contribution of the GJB2-mutations among patients with congenital hearing loss in Yakutia was 49%. The aim of this work was to investigate the molecular genetic basis of hearing loss among GJB2-negative patients. The study included 238 (228 unrelated) GJB2-negative patients, among them we found one family with five affected individuals with juvenile hearing loss of unknown etiology (the disease onset varied from 0 to 8 years). Using a whole exome sequencing (WES), performed in one of affected family members, a novel homozygous c.1121G>A (6p21.1, OMIM 607293) substitution in exon 6 of the CLIC5 gene was detected. This substitution leads to the formation of a premature stop codon at the 374 amino acid position (p.Trp374*) which terminates the synthesis of the polypeptide chain of the CLIC5 protein (NP_001107558.1). To date, only one homozygous mutation c.96T>A (p.Cys32*) was known in human gene CLIC5 which was found in one inbred Turkish family with progressive autosomal recessive deafness, type 103 (DFNB103). In our study, a homozygous variant c.1121G>A (p.Trp374*) was detected in 26 out of 238 GJB2-negative patients in Yakutia (10.9%). Most of homozygous for c.1121G>A patients (19 out of 26) reported about late onset of their hearing loss occurred in postlingual period (averaged 9.7±0.6 years). Audiological examination of 13 out of 26 patients revealed predominantly symmetric sensorineural progressive hearing loss of varying severity (from mild to profound hearing loss). The average prevalence of DFNB103 caused by the homozygous variant c.1121G>A (p.Trp374*) in Yakutia was 0.27±0.053 per 10000 with a maximum accumulation in Eveno-Bytantaysky district (31.39±10.46 per 10000) which referred to the Arctic group of districts where the majority of the population is represented by Evens (53%). This is the first case of the identification of the orphan disease with its accumulation in Arctic part of Russia. In general, the homozygous variant c.1121G>A (p.Trp374*) of the CLIC5 gene can be regarded as causative to DFNB103 with a high contribution to the etiology of hearing impairments in the population of Yakutia.

About the Authors

V. G. Pshennikova
Yakut Scientific Center for Complex Medical Problems; M.K. Ammosov North-Eastern Federal University
Russian Federation


G. P. Romanov
Yakut Scientific Center for Complex Medical Problems; M.K. Ammosov North-Eastern Federal University
Russian Federation


T. M. Nikolaeva
Republican Hospital No. 2 - Center for emergency medical care
Russian Federation


F. M. Teryutin
Yakut Scientific Center for Complex Medical Problems; Republican Hospital No. 2 - Center for emergency medical care
Russian Federation


T. V. Borisova
M.K. Ammosov North-Eastern Federal University
Russian Federation


I. F. Komar’Kov
Genomed Ltd
Russian Federation


A. V. Antonets
Genomed Ltd
Russian Federation


A. V. Solovyev
Yakut Scientific Center for Complex Medical Problems; M.K. Ammosov North-Eastern Federal University
Russian Federation


L. A. Klarov
Yakut Scientific Center for Complex Medical Problems
Russian Federation


A. A. Bondar
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation


I. V. Morozov
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University
Russian Federation


O. L. Posukh
Novosibirsk State University; Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
Russian Federation


E. K. Khusnutdinova
Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences; Bashkir State University
Russian Federation


S. A. Fedorova
Yakut Scientific Center for Complex Medical Problems; M.K. Ammosov North-Eastern Federal University
Russian Federation


N. A. Barashkov
Yakut Scientific Center for Complex Medical Problems; M.K. Ammosov North-Eastern Federal University
Russian Federation


Review

For citations:


Pshennikova V.G., Romanov G.P., Nikolaeva T.M., Teryutin F.M., Borisova T.V., Komar’Kov I.F., Antonets A.V., Solovyev A.V., Klarov L.A., Bondar A.A., Morozov I.V., Posukh O.L., Khusnutdinova E.K., Fedorova S.A., Barashkov N.A. A novel nonsense mutation c.1121G>A (p.Trp374*) in the CLIC5 gene is the main cause of the juvenile autosomal recessive form of deafness (DFNB103) in the Arctic regions of Yakutia. Medical Genetics. 2019;18(10):36-48. (In Russ.)

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ISSN 2073-7998 (Print)