Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Mitochondrion. 2010 Jun;10(4):380-90. doi: 10.1016/j.mito.2010.01.007. Epub 2010 Jan 25.
In this report, we investigated the frequency and spectrum of mitochondrial 12S rRNA variants in a large cohort of 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss. Mutational analysis of 12S rRNA gene in these subjects identified 68 (54 known and 14 novel) variants. The frequencies of known 1555A>G and 1494C>T mutations were 3.96% and 0.18%, respectively, in this cohort with nonsyndromic and aminoglycoside-induced hearing loss. Prevalence of other putative deafness-associated mutation at positions 1095 and 961 were 0.61% and 1.7% in this cohort, respectively. Furthermore, the 745A>G, 792C>T, 801A>G, 839A>G, 856A>G, 1027A>G, 1192C>T, 1192C>A, 1310C>T, 1331A>G, 1374A>G and 1452T>C variants conferred increased sensitivity to ototoxic drugs or nonsyndromic deafness as they were absent in 449 Chinese controls and localized at highly conserved nucleotides of this rRNA. However, other variants appeared to be polymorphisms. Moreover, 65 Chinese subjects carrying the 1555A>G mutation exhibited bilateral and sensorineural hearing loss. A wide range of severity, age-of-onset and audiometric configuration was observed among these subjects. In particular, the sloping and flat-shaped patterns were the common audiograms in individuals carrying the 1555A>G mutation. The phenotypic variability in subjects carrying these 12S rRNA mutations indicated the involvement of nuclear modifier genes, mitochondrial haplotypes, epigenetic and environmental factors in the phenotypic manifestation of these mutations. Therefore, our data demonstrated that mitochondrial 12S rRNA is the hot spot for mutations associated with aminoglycoside ototoxicity.
在这项报告中，我们研究了一个包含 1642 名汉族儿科患者的大样本中，线粒体 12S rRNA 变异的频率和谱。对这些患者的 12S rRNA 基因进行突变分析，发现了 68 种（54 种已知和 14 种新的）变异。在这个有非综合征型和氨基糖苷类诱导性听力损失的患者队列中，已知的 1555A>G 和 1494C>T 突变的频率分别为 3.96%和 0.18%。在这个队列中，其他假定与耳聋相关的位置 1095 和 961 的突变率分别为 0.61%和 1.7%。此外，745A>G、792C>T、801A>G、839A>G、856A>G、1027A>G、1192C>T、1192C>A、1310C>T、1331A>G、1374A>G 和 1452T>C 变异使得对耳毒性药物或非综合征型耳聋更敏感，因为它们在 449 名中国对照中不存在，并且定位于该 rRNA 的高度保守核苷酸上。然而，其他变异似乎是多态性的。此外，65 名携带 1555A>G 突变的中国患者表现为双侧和感音神经性听力损失。这些患者的严重程度、发病年龄和听力图配置差异很大。特别是，携带 1555A>G 突变的个体中常见的听力图是斜率形和扁平形。携带这些 12S rRNA 突变的个体的表型变异性表明，核修饰基因、线粒体单倍型、表观遗传和环境因素参与了这些突变的表型表现。因此，我们的数据表明，线粒体 12S rRNA 是与氨基糖苷类耳毒性相关的突变热点。
