线粒体tRNA^Asp A7551G突变可能是耳聋相关的线粒体基因新突变

Hearing loss may be associated with the novel mitochondrial tRNAAsp A7551G mutation in a Chinese family

目的 通过对携带线粒体tRNA^Asp A7551G突变的母系遗传非综合征型耳聋家系进行临床和分子遗传学特征分析,探讨线粒体tRNA^Asp基因突变对非综合征型耳聋的影响.方法 收集1个携带线粒体tRNA^Asp A7551G突变的非综合征型耳聋家系,对先证者及其家系成员进行听力学检查、线粒体基因组全序列分析和GJB2基因突变检测等.结果 家系内共6人患病,母系成员占4人.先证者线粒体全基因组分析表明,该线粒体基因组含28个多态位点,属于东亚人群A4单体型.其中除A7551G同质性突变外,无其他有功能意义的多态位点.A7551G突变位于线粒体tRNA^Asp反密码子环的反密码子旁高度保守区的第37位,保守性指数为100％且未在正常对照中发现.GJB2基因突变分析发现先证者及家系成员携带有与耳聋相关的235delC、299delAT突变位点.家系内母系成员在发病年龄、听力损失程度和听力曲线上存在较大差异.结论 线粒体tRNA^Asp A7551G突变可能通过改变对tRNA二级结构的修饰作用,影响tRNA结构的稳定性,最终导致线粒体功能异常,引起耳聋表型,该突变可能是与耳聋相关的线粒体基因新突变.

Objective We reported here the clinical and genetic evaluations as well as mutational analysis of mitochondrial DNA （mtDNA） in a Chinese family with maternally transmitted non-syndromic hearing loss and investigated the influence of the mitochondrial tRNAAsp A7551G mutation to the phenotypic manifestation of the deafness. Methods One Chinese Han pedigrees of maternally transmitted nonsyndromic hearing loss were collected. The proband and family members underwent clinical, genetic, and molecular evaluations, such as audiological examinations, mutational analysis of mitochondrial genome and mutational analysis of GJB2 gene. Results Six people of this pedigree suffered from hearing loss, including four matrilineal members, and others did not have significant clinical abnormalities. Sequence analysis of the complete mitoehondrial genome in the proband showed that there were 28 mtDNA polymorphisms belonging to East-Asian haplogroup A4. In addition to the A7551G homogeneity mutation, there were no other functionally significant variants found in this family. The A7551C mutation located immediately at the three prime end to the anticodon, corresponding with the conventional position 37 of tRNAAsp, and its＇ CI value was 100% compared with other 15 primate species. The A7551G mutation was absent in other Chinese controls. The mutations on GJB2 were detected by direct sequence analysis, GJB2 235delC and 299de1AT which was associated with hearing loss were fimnd in the geneomic DNA of the proband and some matrilineal members. Clinical evaluation showed a variable phenotype of severity, age-at-onset and audiometric configuration of hearing loss in the matrilineal relatives in these families. Conclusions The A7551G mutation may modify the secondary structure of the tRNA, and affect the stabilization of tRNA Asp ,produee non-nornml functional tRNAAsp uhimately. And it may cause the phenotypic manifestation of the deafness that associated with A7551G mutation. Therefore, the mitoehondrial tRNAAsp A7551G mutation may be a new mitochondrial mutation for hearing loss.