Barashkov Nikolay A, Pshennikova Vera G, Posukh Olga L, Teryutin Fedor M, Solovyev Aisen V, Klarov Leonid A, Romanov Georgii P, Gotovtsev Nyurgun N, Kozhevnikov Andrey A, Kirillina Elena V, Sidorova Oksana G, Vasilyevа Lena M, Fedotova Elvira E, Morozov Igor V, Bondar Alexander A, Solovyevа Natalya A, Kononova Sardana K, Rafailov Adyum M, Sazonov Nikolay N, Alekseev Anatoliy N, Tomsky Mikhail I, Dzhemileva Lilya U, Khusnutdinova Elza K, Fedorova Sardana A
Department of Molecular Genetics, Federal State Budgetary Scientific Institution "Yakut Science Centre of Complex Medical Problems," Yakutsk, Russian Federation.
Laboratory of Molecular Biology, Institute of Natural Sciences, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation.
PLoS One. 2016 May 25;11(5):e0156300. doi: 10.1371/journal.pone.0156300. eCollection 2016.
Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts-296, Russians-51, mixed and other ethnicities-46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.
已知编码连接蛋白26的GJB2基因中的致病变异是听力障碍（HI）的主要原因。在GJB2基因中已鉴定出300多种等位基因变体。GJB2基因的频谱和等位基因频率在全球不同种族之间存在显著差异。到目前为止，位于俄罗斯亚北极地区的萨哈共和国（雅库特）尚未对GJB2基因第1外显子、第2外显子及其侧翼内含子区域的致病变异频谱和频率进行详尽描述。对393例听力障碍患者（雅库特人296例、俄罗斯人51例、混血及其他种族46例）以及187名雅库特族（n = 107）和俄罗斯族（n = 80）听力正常个体的GJB2基因非编码区和编码区进行了全序列测序。在总样本（n = 580）中，我们发现了GJB2基因的12个等位基因变体，其中8个是隐性致病变异。在393例患者中的192例（48.85%）中发现了10种GJB2基因双等位基因隐性致病变异的基因型（纯合或复合杂合状态）。我们发现，雅库特患者中最常见的GJB2致病变异是c.-23+1G>A（51.82%），第二常见的是c.109G>A（2.37%），其次是c.35delG（1.64%）。在俄罗斯患者中，致病变异с.35delG（22.34%）、c.-23+1G>A（5.31%）和c.313_326del14（2.12%）最为常见。雅库特对照组中c.-23+1G>A和с.109G>A致病变异的携带频率分别为10.20%和2.80%。俄罗斯对照组中с.35delG和c.101T>C的携带频率相同（2.5%）。我们发现，在所有先前研究的亚洲地区中，萨哈共和国人群中GJB2基因致病变异对听力障碍的贡献率（48.85%）最高。我们认为，c.-23+1G>A致病变异在雅库特原住民中的广泛积累（占患者所有突变染色体的92.20%）以及对照组中极高的（10.20%）携带频率可能表明生活在亚北极气候中的c.-23+1G>A携带者具有可能的选择优势。
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