Department of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Mitochondrion. 2009 Nov;9(6):418-28. doi: 10.1016/j.mito.2009.07.006. Epub 2009 Aug 12.
Mutations in mitochondrial DNA (mtDNA) are associated with sensorineural hearing loss. In this study, we traced the origin of the 12S rRNA C1494T mutation through analysis of the clinical, genetic, and molecular characteristics of 13 Han Chinese pedigrees with aminoglycoside-induced and non-syndromic bilateral hearing loss that were selected by C1494T screening in 3133 subjects with non-syndromic hearing impairment from 27 regions of China (13/3133). Clinical evaluation revealed the variable phenotypes of hearing impairment including severity, age-of-onset, and audiometric configuration in these subjects. Through the whole mitochondrial genome DNA sequence analysis, we identified two evolutionarily conservative variants in protein-coding genes: tRNA(Ala) T 5628C and tRNA(Tyr) A5836G mutations. However, the pedigrees with these mutations did not have a higher or lower penetrance of deafness than in other pedigrees. These results suggested that both T 5628C and A5836G mutations might not significantly modify the manifestation of the C1494T mutation. Sequencing analysis of the whole mitochondrial genome of the probands showed that 13 pedigrees from seven different provinces were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms, including haplogroups A, B, D, D4, D4b2, F1, M, M7c, N9a1, and H2b. This result suggested that the C1494T mutation occurred sporadically with multi-origins through the evolution of the mtDNA in China, and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. In addition, the lack of a significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. Therefore, the aminoglycosides is solo well-established factor to contribute to the deafness manifestation of the C1494T mutation, and prevention by avoiding the administration of aminoglycosides in individuals carrying C1494T mutation is the most effective way to protect their vulnerability to deafness.
线粒体 DNA（mtDNA）突变与感音神经性听力损失有关。在这项研究中，我们通过分析 13 个汉族家系的临床、遗传和分子特征，追溯了 12S rRNA C1494T 突变的起源。这些家系是通过对来自中国 27 个地区的 3133 名非综合征性听力障碍患者（13/3133）进行 C1494T 筛查，选择出的氨基糖苷类诱导的和非综合征性双侧听力损失患者。临床评估显示，这些患者的听力障碍表型存在差异，包括严重程度、发病年龄和听力图模式。通过全线粒体基因组 DNA 序列分析，我们在蛋白质编码基因中发现了两个进化保守的变异：tRNA（Ala）T5628C 和 tRNA（Tyr）A5836G 突变。然而，携带这些突变的家系的耳聋外显率并不高于其他家系。这些结果表明，T5628C 和 A5836G 突变可能不会显著改变 C1494T 突变的表现。对先证者的全线粒体基因组进行测序分析显示，来自 7 个不同省份的 13 个家系根据独特的 mtDNA 多态性分为 10 个单倍群，包括单倍群 A、B、D、D4、D4b2、F1、M、M7c、N9a1 和 H2b。这表明 C1494T 突变是通过中国 mtDNA 的进化随机发生的，并具有多起源性，这些 mtDNA 单倍群特异性变异可能不会在这些具有不同耳聋外显率的中国家系中对 C1494T 突变的表型表达起重要作用。此外，GJB2 基因中没有明显的突变，排除了 GJB2 可能参与 C1494T 突变表型表达的可能性。因此，氨基糖苷类药物是导致 C1494T 突变致聋表现的明确因素，避免携带 C1494T 突变的个体使用氨基糖苷类药物是保护其易感性的最有效方法。
