线粒体DNAT1095C突变的耳聋患者的临床特征及mtDNA序列分析  

Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation

作　　者：赵立东[1] 杨伟炎[1] 李荣华 王秋菊[1] 钱亚萍 管敏鑫 

机构地区：[1]中国人民解放军总医院耳鼻咽喉科研究所,北京100853 [2]Division and Programin Human Genetics and Center for Hearing and Deafness Research,Cincinnati Children’s Hospital Medical Center,Cincinnati,Ohio,USA [3]Division and Programin Human Genetics and Center for Hearing and Deafness Research,Cincinnati Children’s Hospital Medical Center,Cincinnati,Ohio,USA Department of Pediatrics,University of Cincinnati College of Medicine,Cincinnati,Ohio,USA

出　　处：《中华耳科学杂志》2005年第4期253-259,共7页Chinese Journal of Otology

基　　金：美国国立卫生研究院基金DC04958;美国国立耳聋和其他交流障碍疾患研究所基金DC05230

摘　　要：目的分析3例携带线粒体12SrRNA基因T1095C突变的耳聋患者的临床特征、其线粒体基因组的全序列特征以及T1095C突变与对非综合征型—耳聋之间的关系。方法对从门诊收集的188例耳聋患者的血样进行线粒体DNA12SrRNA基因突变筛查,发现三例携带T1095C突变,推测T1095C突变所引起的12SrRNA二级结构变化及其可能的线粒体功能的变化。对这三例患者的线粒体基因组进行全序列测定,同时对其临床资料进行分析。结果从门诊收集的188例患者的血样中,发现3例患者携带线粒体12SrRNAT1095C突变,临床表现型的评估表明,这些患者的听力损失(包括发病年龄,听力图)的类型不一。序列分析表明这三个患者的线粒体基因组除都有T1095C的突变之外,其线粒体DNA的多态位点还显示独特的多态性。在364个国人的正常对照组中,没有发现该突变。结论T1095C在这些遗传背景不同的有听力损失的家庭中出现强烈的提示这个突变是导致听力损失的致病因素,T1095C突变可能与非综合征型耳聋有关。在这些线粒体DNA中,还有一些碱基突变,如16SrRNA中的A2238G和T2885C以及在CO2(氧化磷酸化复合体2)基因中的第175位氨基酸由Ile变成Val,在ATP合成酶6基因中的第16位氨基酸由Phe变成Leu,以及在ND6基因中的第112位氨基酸由Val变成Met都位于进化上高度保守的区域,这些突变可能对这3位患者耳聋的临床表型起了一部分作用。Mutations in mitochondrial DNA （mtDNA）, particularly those in the 12S rRNA gene, have been shown to be associated with sensorineural hearing loss. Here we report the clinical and sequence analysis of the entire mitochondrial genome in three Chinese subjects with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluation showed a variable phenotype of hearing impairment including the age of onset and audiometric configuration in these subjects. Sequence analysis of the complete mitochondrial genomes in three subjects showed the distinct sets of mtDNA polymorphism, in addition to the identical mitochondrial 12S rRNA T1095C matation. This mutation was previously identified to be associated with hearing impairment in three families from different genetic backgrounds. The T1095C mutation was absent in 364 Chinese controls. In fact, the occurrence of the T1095C mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. Among other nucleotide changes, the A2238G and T2885C mutations in the 16S rRNA, the I175V mutation in the CO2, the F16L mutation in the A6 and the V112M mutation in the ND6 exhibited a high evolutionary conservation. These data suggest that the T1095C mutation may be associated with aminoglycoside-induced and non-syndromic hearing impairments and A2238G and T2885C mutations in the 16S rRNA, the I175V mutation in the CO2, the F16L mutation in the A6 and the V112M mutation in the ND6 may contribute to the phenotypic expression of the T1095C mutation in these subjects.

关 键 词：耳聋 线粒体DNA 突变 氨基糖甙类抗生素 

分 类 号：R587.1[医药卫生—内分泌] R373.21[医药卫生—内科学]