Tang Xiaowen, Zheng Jing, Ying Zhengbiao, Cai Zhaoyang, Gao Yinglong, He Zheyun, Yu Han, Yao Juan, Yang Yaling, Wang Hui, Chen Ye, Guan Min-Xin
Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Mitochondrion. 2015 Jul;23:17-24. doi: 10.1016/j.mito.2015.05.001. Epub 2015 May 10.
Mutations in the mitochondrial DNA have been associated with hearing loss. However, the prevalence and spectrum of mitochondrial tRNA mutations in hearing-impaired subjects are poorly understood. In this report, we have investigated the prevalence and spectrum of mitochondrial tRNA(Ser(UCN)) mutations in a large cohort of 2651 Han Chinese subjects with hearing loss. The clinical evaluation showed that 744 subjects (432 males and 312 females) had a history of exposure to aminoglycosides and other probands exhibited nonsyndromic hearing loss. Mutational analysis of tRNA(Ser(UCN)) gene identified 9 (8 known and 1 novel) variants. The prevalence of the known deafness-associated 7511T>C, 7505T>C and 7445A>C mutations was 0.04%, 0.04% and 0.04%, respectively. Other variants were evaluated by the evolutionary conservation, allelic frequency of Chinese controls, potential structural and functional alterations and pedigree analysis. Three variants were polymorphisms, while the 7444G>A, 7471DelG and 7496A>G variants were putative deafness-associated mutations. These putative deafness-associated variants accounted for 0.68% cases of hearing-impaired subjects in this cohort. The low penetrance of hearing loss in pedigrees carrying one of these putative deafness-associated mutations indicated that the mutation(s) is necessary but itself insufficient to produce a clinical phenotype. Other genetic or environmental factor(s) may influence the phenotypic manifestation of these tRNA(Ser(UCN)) mutations. Moreover, mtDNAs in 20 probands carrying one of the putative deafness-associated mutations were widely dispersed among 8 Eastern Asian haplogroups. In particular, the occurrences of haplogroups D4a, M22, and H2 in patients carrying the deafness-associated variants were higher than those in Chinese controls. These data further support that the mitochondrial tRNA(Ser(UCN)) gene is the hot spot for mutations associated with hearing loss. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of hearing loss.
线粒体DNA突变与听力损失有关。然而，听力受损受试者中线粒体tRNA突变的患病率和谱型尚不清楚。在本报告中，我们调查了2651名中国汉族听力损失受试者队列中线粒体tRNA(Ser(UCN))突变的患病率和谱型。临床评估显示，744名受试者（432名男性和312名女性）有氨基糖苷类药物接触史，其他先证者表现为非综合征性听力损失。tRNA(Ser(UCN))基因的突变分析鉴定出9个（8个已知和1个新的）变异。已知的与耳聋相关的7511T>C、7505T>C和7445A>C突变的患病率分别为0.04%、0.04%和0.04%。通过进化保守性、中国对照组的等位基因频率、潜在的结构和功能改变以及家系分析对其他变异进行了评估。三个变异为多态性，而7444G>A、7471DelG和7496A>G变异为推定的与耳聋相关的突变。这些推定的与耳聋相关的变异占该队列中听力受损受试者病例的0.68%。携带这些推定的与耳聋相关突变之一的家系中听力损失的低外显率表明，该突变是必要的，但本身不足以产生临床表型。其他遗传或环境因素可能影响这些tRNA(Ser(UCN))突变的表型表现。此外，携带推定的与耳聋相关突变之一的20名先证者的线粒体DNA广泛分布在8个东亚单倍群中。特别是，携带耳聋相关变异的患者中单倍群D4a、M22和H2的发生率高于中国对照组。这些数据进一步支持线粒体tRNA(Ser(UCN))基因是与听力损失相关的突变热点。因此，我们的发现可能为进一步了解听力损失的病理生理学和管理提供有价值的信息。
