修饰因子对线粒体DNA突变致聋的影响  

Modifier factors influencing the phenotypic manifestation of the deafness-associated mitochondrial DNA mutations

作　　者：杨爱芬[1] 郑静[1] 吕建新[1] 管敏鑫[1,2] 

机构地区：[1]浙江省温州医学院Attardi线粒体生物医学研究院和浙江省医学遗传学重点实验室,325035 [2]Division of Human Genetics,Cincinnati Children's Hospital Medical Center,Cincinnati,Ohio 45229 USA

出　　处：《中华医学遗传学杂志》2011年第2期165-171,共7页Chinese Journal of Medical Genetics

基　　金：国家＂973＂重大基础研究前期研究专项（2004CCA02200）;浙江省医药卫生科学研究基金（2006A100）;浙江省＂钱江人才计划＂择优资助项目（2006R10021）;浙江省重大科技专项社会发展项目（2007C13021）

摘　　要：线粒体DNA突变是引起感音神经性耳聋的重要原因之一,这些突变主要位于线粒体12SrRNA和tRNA基因上.其中12S rRNA基因上的同质性A1555G和C1494T突变与氨基糖甙类抗生素造成的耳聋相关.携带这两个突变的个体对耳毒性药物高度敏感,导致临床上常见的＂一针致聋＂现象.但携带A1555G或C1494T突变的个体在没用药的情况下也能产生非综合征型耳聋,而且同一家系内和不同家系间的母系成员在听力损失程度、发病年龄及听力曲线上存在很大差异.这些数据表明A1555G或C1494T突变是导致非综合征型耳聋发生的首要因子,其他修饰因子包括氨基糖甙类抗生素、线粒体DNA单倍型和核修饰基因等,在线粒体12S rRNA A1555G或C1494T突变相关的耳聋表型表达上起协同作用.作者简要介绍了这些因素对线粒体DNA突变致聋的影响以及母系遗传性耳聋发生的可能致病机制.Mutations in the mitochondrial DNA have been found to be one of the most important causes of sensorineural hearing loss. In particular, these mutations often occur in the mitochondrial 12S rRNA and tRNA genes. Of these, the homoplasmic A1555G and C1494T mutations in the 12S rRNA have been associated with both aminoglycoside induced and nonsyndromic hearing impairment in many families worldwide. Children carrying the A1555G or C1494T mutation are susceptible to the exposure of ototoxic drugs, thereby inducing or worsening hearing loss. Individuals harboring A1555G or C1494T mutation can also develop hearing loss even in the absence of aminoglycoside exposure. However, matrilineal relatives of intra-families or inter-families carrying the A1555G or C1494T mutation exhibit a wide range of severity,age-at-onset, and audiometric configuration of hearing impairment. These indicate that the A1555G or C1494T mutation is a primary factor underlying the development of deafness but insufficient to produce the clinical phenotype. Thus, other modifier factors, such as aminoglycoside （s）, mitochondrial DNA haplotype（s） or nuclear modifier gene（s）, play a role in the phenotypic expression of the deafness-associated mitochondrial 12S rRNA A1555G or C1494T mutation. In this review, we summarize the modifier factors for the phenotypic expression of deafness-associated 12S rRNA A1555G and C1494T mutations and propose the molecular pathogenetic mechanism of maternally inherited deafness.

关 键 词：线粒体DNA突变 非综合征型耳聋 氨基糖甙类抗生素 线粒体DNA单倍型 核修饰基因 

分 类 号：R764[医药卫生—耳鼻咽喉科]