Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation
Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation
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13个中国家系的线粒体单倍型和表型可能提示线粒体C1494T突变的多源进化
DOI：
10.1016/j.mito.2009.07.006
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发表时间：
2009-11-01
期刊：
影响因子：
4.4
通讯作者：
Dai, Pu
中科院分区：
文献类型：
--
作者：
Zhu, Yuhua;Li, Qi;Dai, Pu
线粒体DNA（mtDNA）突变与感音神经性听力损失有关。在这项研究中，我们通过分析13个中国汉族家系的临床、遗传和分子特征来追踪12S rRNA C1494T突变的起源，这些家系是在中国27个地区的3133名非综合征性听力损害受试者中通过C1494T筛查选出的。临床评估显示，这些受试者的听力损害的可变表型，包括严重程度，发病年龄和听力配置。通过对线粒体全基因组DNA序列的分析，我们发现了两个进化上保守的蛋白质编码基因突变：tRNA（Ala）T5628C和tRNA（Tyr）A5836G突变。然而，这些突变的家系并没有比其他家系有更高或更低的耳聋发生率。这些结果表明，T5628C和A5836G突变可能不会显着改变C1494T突变的表现。先证者的线粒体全基因组测序结果显示，来自7个不同省份的13个家系可分为10个单倍型群，包括A、B、D、D4、D4b2、F1、M、M7 c、N9a1和H2 B。提示C1494T突变在中国人mtDNA进化过程中具有多源性和偶发性，这些mtDNA单倍型群特异性变异体可能对中国人不同听力损失家系中C1494T突变的表型表达没有重要作用。此外，GJB2基因中缺乏显著突变排除了GJB2参与受影响受试者中C1494T突变表型表达的可能性。因此，氨基糖苷类是导致C1494T突变耳聋表现的唯一公认因素，通过避免给予携带C1494T突变的个体氨基糖苷类进行预防是保护其耳聋易感性的最有效方法。(C)2009 Elsevier B.V.和线粒体研究学会。All rights reserved.
Mutations in mitochondrial DNA (mtDNA) are associated with sensorineural hearing loss. In this study, we traced the origin of the 12S rRNA C1494T mutation through analysis of the clinical, genetic, and molecular characteristics of 13 Han Chinese pedigrees with aminoglycoside-induced and non-syndromic bilateral hearing loss that were selected by C1494T screening in 3133 subjects with non-syndromic hearing impairment from 27 regions of China (13/3133). Clinical evaluation revealed the variable phenotypes of hearing impairment including severity, age-of-onset, and audiometric configuration in these subjects. Through the whole mitochondrial genome DNA sequence analysis, we identified two evolutionarily conservative variants in protein-coding genes: tRNA(Ala) T 5628C and tRNA(Tyr) A5836G mutations. However, the pedigrees with these mutations did not have a higher or lower penetrance of deafness than in other pedigrees. These results suggested that both T 5628C and A5836G mutations might not significantly modify the manifestation of the C1494T mutation. Sequencing analysis of the whole mitochondrial genome of the probands showed that 13 pedigrees from seven different provinces were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms, including haplogroups A, B, D, D4, D4b2, F1, M, M7c, N9a1, and H2b. This result suggested that the C1494T mutation occurred sporadically with multi-origins through the evolution of the mtDNA in China, and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. In addition, the lack of a significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. Therefore, the aminoglycosides is solo well-established factor to contribute to the deafness manifestation of the C1494T mutation, and prevention by avoiding the administration of aminoglycosides in individuals carrying C1494T mutation is the most effective way to protect their vulnerability to deafness. (C) 2009 Elsevier B.V. and Mitochondria Research Society. All rights reserved.