Dai Pu, Liu Xin, Han Dongyi, Qian Yaping, Huang Deliang, Yuan Huijun, Li Weiming, Yu Fei, Zhang Ruining, Lin Hongyan, He Yong, Yu Youjun, Sun Quanzhu, Qin Huaiyi, Li Ronghua, Zhang Xin, Kang Dongyang, Cao Juyang, Young Wie-Yen, Guan Min-Xin
Department of Otolaryngology, Chinese PLA General Hospital, Beijing, China.
Biochem Biophys Res Commun. 2006 Feb 3;340(1):194-9. doi: 10.1016/j.bbrc.2005.11.156.
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 16 Chinese pedigrees (a total of 246 matrilineal relatives) with aminoglycoside-induced impairment. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects, although these subjects share some common features: being bilateral and sensorineural hearing impairment. Strikingly, these Chinese pedigrees exhibited extremely low penetrance of hearing loss, ranging from 4% to 18%, with an average of 8%. In particular, nineteen of 246 matrilineal relatives in these pedigrees had aminoglycoside-induced hearing loss. Mutational analysis of the mtDNA in these pedigrees showed the presence of homoplasmic 12S rRNA A1555G mutation, which has been associated with hearing impairment in many families worldwide. The extremely low penetrance of hearing loss in these Chinese families carrying the A1555G mutation strongly supports the notion that the A1555G mutation itself is not sufficient to produce the clinical phenotype. Children carrying the A1555G mutation are susceptible to the exposure of aminoglycosides, thereby inducing or worsening hearing impairment, as in the case of these Chinese families. Using those genetic and molecular approaches, we are able to diagnose whether children carry the ototoxic mtDNA mutation. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside therapy, and eventually to decrease the incidence of deafness.
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16个中国家系（共246名母系亲属）氨基糖苷类药物所致听力损害的临床、遗传和分子特征。临床评估显示，这些受试者的听力损害表型各异，包括听力图形态，尽管他们有一些共同特征：双侧感音神经性听力损害。引人注目的是，这些中国家系的听力损失外显率极低，为4%至18%，平均为8%。特别是，这些家系中的246名母系亲属中有19人患有氨基糖苷类药物所致听力损失。对这些家系的mtDNA进行突变分析，发现存在纯合的12S rRNA A1555G突变，该突变在全球许多家族中都与听力损害有关。这些携带A1555G突变的中国家系中听力损失的极低外显率有力地支持了这样一种观点，即A1555G突变本身不足以产生临床表型。携带A1555G突变的儿童易受氨基糖苷类药物暴露的影响，从而诱发或加重听力损害，就像这些中国家系的情况一样。通过这些遗传和分子方法，我们能够诊断儿童是否携带耳毒性mtDNA突变。因此，这些数据为预测哪些个体有耳毒性风险、提高氨基糖苷类药物治疗的安全性以及最终降低耳聋发病率提供了有价值的信息和技术。
