Young Wie-Yen, Zhao Lidong, Qian Yaping, Li Ronghua, Chen Jing, Yuan Huijun, Dai Pu, Zhai Suoqiang, Han Dongyi, Guan Min-Xin
Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Am J Med Genet A. 2006 Oct 15;140(20):2188-97. doi: 10.1002/ajmg.a.31434.
We report here on the clinical, genetic, and molecular characterization of three Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing loss. Clinical evaluation revealed the variable phenotype of hearing loss including severity, age-at-onset, audiometric configuration in these subjects. Penetrances of hearing loss in BJ107, BJ108, and BJ109 pedigrees are 35%, 63%, and 67%, respectively. Mutational analysis of the complete mitochondrial genomes in these pedigrees showed the identical homoplasmic A1555G mutation and distinct sets of mitochondrial DNA (mtDNA) variants belonging to haplogroups N, F, and M, respectively. Of these variants, the A14693G mutation in the tRNA(Glu), the T15908C mutation in the tRNA(Thr), and the T10454C mutation in the tRNA(Arg) are of special interest as these mutations occur at positions which are highly evolutionarily conserved nucleotides of corresponding tRNAs. These homoplasmic mtDNA mutations were absent among 156 unrelated Chinese controls. The A14693G and T10454C mutations occur at the highly conserved bases of the TpsiC-loop of tRNA(Glu) and tRNA(Arg), respectively. Furthermore, the T15908C mutation in the tRNA(Thr) disrupts a highly conserved A-U base-pairing at the D-stem of this tRNA. The alteration of structure of these tRNAs by these mtDNA mutations may lead to a failure in tRNA metabolism, thereby causing impairment of mitochondrial translation. Thus, mitochondrial dysfunctions, caused by the A1555G mutation, would be worsened by these mtDNA mutations. Therefore, these mtDNA mutations may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated 12S rRNA A1555G mutation in those Chinese pedigrees.
我们在此报告三个汉族家系氨基糖苷类药物所致非综合征性听力损失的临床、遗传和分子特征。临床评估显示这些受试者听力损失的表型各异，包括严重程度、发病年龄、听力图形态。BJ107、BJ108和BJ109家系中听力损失的外显率分别为35%、63%和67%。对这些家系的完整线粒体基因组进行突变分析，发现了相同的纯合A1555G突变以及分别属于单倍群N、F和M的不同线粒体DNA（mtDNA）变异组。在这些变异中，tRNA（Glu）中的A14693G突变、tRNA（Thr）中的T15908C突变以及tRNA（Arg）中的T10454C突变特别值得关注，因为这些突变发生在相应tRNA高度进化保守核苷酸的位置。在156名无关的中国对照者中未发现这些纯合mtDNA突变。A14693G和T10454突变分别发生在tRNA（Glu）和tRNA（Arg）TpsiC环的高度保守碱基处。此外，tRNA（Thr）中的T15908C突变破坏了该tRNA D茎处高度保守的A - U碱基配对。这些mtDNA突变导致的这些tRNA结构改变可能会导致tRNA代谢失败，从而引起线粒体翻译受损。因此，由A1555G突变引起的线粒体功能障碍会因这些mtDNA突变而恶化。所以，这些mtDNA突变可能在增加那些中国家系中与耳聋相关的12S rRNA A1555G突变的外显率和表现度方面具有潜在的修饰作用。
