Extremely low penetrance of deafness associated with the mitochondrial 12S rRNA T1095C mutation in three Chinese families

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here the clinical, genetic, and molecular characterization of three Chinese pedigrees (a total of 43 matrilineal relatives) with aminoglycoside-induced impairment. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects, although these subjects shared some common features: being bilateral and sensorineural hearing impairment. Strikingly, only probands of these Chinese pedigrees exhibited severe to profound hearing loss. Mutational analysis of the mtDNA in these pedigrees showed the presence of homoplasmic 12S rRNA T1095C mutation, which has been associated with hearing impairment in several families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the identical homoplasmic T1095C mutation and distinct sets of mitochondrial DNA (mtDNA) variants belonging to haplogroups M11C. Despite the presence of several highly evolutionarily conservative variants in protein-encoding genes and 16S rRNA gene, the extremely low penetrance of hearing loss with the T1095C mutation implies that the mitochondrial variants may not play an important role in the phenotypic expression of the T1095C mutation in these Chinese families. However, the history of exposure to aminoglycosides in these three hearing-impaired subjects suggested that the aminoglycosides very likely are the cause of hearing loss. (c) 2006 Elsevier Inc. All rights reserved.

线粒体DNA（mtDNA）突变已被发现与感音神经性听力损失有关。我们在此报告三个中国家系（共43名母系亲属）氨基糖苷类药物诱导损伤的临床、遗传和分子特征。临床评估显示这些受试者听力损伤的表型各异，包括听力测定配置，尽管他们有一些共同特征：双侧感音神经性听力损伤。引人注目的是，只有这些中国家系的先证者表现出重度至极重度听力损失。对这些家系的mtDNA突变分析显示存在同质性的12S rRNA T1095C突变，该突变已在几个家族中与听力损伤有关。对这些家系完整线粒体基因组的序列分析显示存在相同的同质性T1095C突变以及属于单倍群M11C的不同线粒体DNA（mtDNA）变异组。尽管在编码蛋白质的基因和16S rRNA基因中存在几个高度进化保守的变异，但T1095C突变导致听力损失的外显率极低，这意味着线粒体变异在这些中国家庭中T1095C突变的表型表达中可能不起重要作用。然而，这三名听力受损受试者的氨基糖苷类药物接触史表明，氨基糖苷类药物很可能是听力损失的原因。（c）2006爱思唯尔公司。保留所有权利。