Unique Mutational Spectrum of the GJB2 Gene and Its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys)

Abstract

Mutations in the GJB2 gene are the main cause for nonsyndromic autosomal recessive deafness 1A (DFNB1A) in many populations. GJB2 mutational spectrum and pathogenic contribution are widely varying in different populations. Significant efforts have been made worldwide to define DFNB1A molecular epidemiology, but this issue still remains open for some populations. The main aim of study is to estimate the DFNB1A prevalence and GJB2 mutational spectrum in Tuvinians—an indigenous population of the Tyva Republic (Southern Siberia, Russia). Sanger sequencing was applied to analysis of coding (exon 2) and non-coding regions of GJB2 in a cohort of Tuvinian patients with hearing impairments (n = 220) and ethnically matched controls (n = 157). Diagnosis of DFNB1A was established for 22.3% patients (28.8% of familial vs 18.6% of sporadic cases). Our results support that patients with monoallelic GJB2 mutations (8.2%) are coincidental carriers. Recessive mutations p.Trp172Cys, c.-23+1G>A, c.235delC, c.299_300delAT, p.Val37Ile and several benign variants were found in examined patients. A striking finding was a high prevalence of rare variant p.Trp172Cys (c.516G>C) in Tuvinians accounting for 62.9% of all mutant GJB2 alleles and a carrier frequency of 3.8% in controls. All obtained data provide important targeted information for genetic counseling of affected Tuvinian families and enrich current information on variability of GJB2 worldwide.

High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

“…We found three GJB2 mutations, c.516G>C, c.-23+1G>A, and c.235delC to be predominant in deaf Tuvinian and Altaian patients [ 10 , 41 , 42 ]. Tuvinians and Altaians are the indigenous Turkic-speaking populations of two neighboring federal subjects of the Russian Federation, the Tyva Republic (Tuva) and the Altai Republic, respectively, which are located in Southern Siberia.…”

“…The GJB2 variant c.516G>C (p.Trp172Cys, rs1302739538) accounts for 62.9% and 29.6% of all mutant GJB2 alleles detected in deaf Tuvinian and Altaian patients, respectively, and the carrier frequencies of c.516G>C are 3.8% and 0.5% in the corresponding ethnically matched controls [ 41 , 42 ]. The c.516G>C substitution leads to a replacement of an aromatic non-polar tryptophan with a small polar cysteine at conservative amino acid position 172 (p.Trp172Cys) in the second extracellular loop of protein connexin 26 (Cx26).…”

“…The pathogenic contribution of the GJB2 mutations to deafness and their carrier frequencies were evaluated in our preliminary studies in indigenous populations of Southern Siberia (Tuvinians and Altaians) and three GJB2 mutations (c.516G>C, c.-23+1G>A, c.235delC) were found to be common [ 10 , 41 , 42 ]. For the analysis of haplotypes bearing these mutations, we recruited in total 28 unrelated deaf patients who were homozygous for c.516G>C (seventeen Tuvinians and one Altaian), for c.-23+1G>A (six Tuvinians) or for c.235delC (four Altaians).…”

“…Since population growth rates for Tuvinian and Altaian populations could not be reliably estimated because of very limited knowledge of demographic variation of these populations along their history, we analyzed the haplotype data using several plausible growth rates: 0.05, 0.1, and 0.2. The parameter “proportion of population sampled” for each of three mutations (c.516G>C, c.-23+1G>A, c.235delC) was calculated on the basis of our previous data [ 10 , 41 , 42 ]. The contemporary population sizes for Tuvinians and Altaians according to the 2010 census were 249299 and 68814 peoples, respectively.…”

“…In our recent study, we evaluated the spectrum and frequency of the GJB2 gene variants in a large cohort of deaf Tuvinian patients and the ethnically matched controls from the Tyva Republic (Southern Siberia, Russia) [ 41 ]. A striking finding was a high prevalence of rare specific variant c.516G>C (p.Trp172Cys) in the GJB2 gene accounting for 62.9% of all mutant GJB2 alleles found in Tuvinian patients and having carrier frequency of 3.8% in controls.…”