与氨基糖甙类抗生素耳毒性相关的线粒体12S rRNA突变的流行病学特征

线粒体DNA（mtDNA）12SrRNA是氨基糖甙类抗生素导致的非综合征型听力损失的一个突变热点区域。在这些突变位点中，位于12SrRNA高度保守的解码区的同质性的A1555G和C1494T突变与耳聋相关，这两个突变导致很多患者的氨基糖甙类抗生素中毒性耳聋。A1555G突变和C1494T突变会在12SrRNA的高度保守的A位形成新的1494C—G1555或1494U—A1555碱基对。这些改变使得12SrRNA在二级结构上与细菌的16srRNA的相应区域的二级结构更加相似．因此．由于C1494T和A1555G突变在12SrRNA形成U—A和G—C配对使得氨基糖甙类抗生素的结合更加容易，这就是为何携带这些突变的人在接触了氨基糖甙类抗生素时会出现或加重耳聋的原因。携带C1494T和A1555G突变的细胞的生化特征是线粒体蛋白质合成的异常并随之引起细胞的呼吸功能异常。而且，当用含高浓度的巴龙霉素或新霉素的DMEM培养基来培养携带这两个突变的细胞系时，可以观察到这些细胞与对照细胞系相比会出现生长缺陷和线粒体内蛋白的翻译异常。这些观察为以下结论提供了直接的遗传和生化方面的证据．即A1555G和C1494T突变是导致氨基糖甙类抗生素诱导的非综合征型耳聋的致病性的mtDNA突变。而且，这些研究数据还为我们进行以下预测提供了有价值的信息和方法：（1）哪些患者有耳毒性风险；（2）提高使用氨基糖甙类抗生素治疗时的安全性；（3）逐渐减少耳聋的发生率。

Mitochondrial DNA mutations associated with aminoglycoside ototoxicity

The mitochondrial DNA 12S rRNA has been shown to the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of those, the homoplasmic A 1555G and C 1494T mutations at a highly conserved decoding region of the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss. These two mutations account for significant cases of aminoglycoside ototoxicity. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U-A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Biochemical characterization demonstrated an impairment of mitochondrial protein synthesis and subsequent defects in respiration in cells carrying C1494T or A1555G mutation. Further- more, the growth defect and impairment of mitochondrial translation in DMEM medium in the presence of high concentration of paromomycin or neomycin were observed in cell lines carrying the A1555G or C1494T mutation as compared to the average rate in control cell lines. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. 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 antibiotic therapy, and eventually to decrease the incidence of deafness.