25个携带线粒体12S rRNA A1555G突变的中国汉族非综合征型耳聋家系  

Mitochondrial 12S rRNA A1555G mutation associated with nonsyndromic hearing loss in twenty-five Han Chinese pedigrees

作　　者：彭光华[1,2] 郑斌娇[3] 方芳[3] 伍越[3] 梁玲芝[3] 郑静[3,4] 南奔宇[1] 余啸[1] 唐霄雯[3] 朱翌[5] 吕建新[3] 陈波蓓[1] 管敏鑫[3,4] 

机构地区：[1]温州医学院附属第二医院附属育英儿童医院耳鼻喉科,温州325027 [2]余姚市人民医院耳鼻咽喉科,宁波315400 [3]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,温州325035 [4]浙江大学生命科学学院,杭州310058 [5]温州医学院附属第一医院耳鼻喉科,温州325027

出　　处：《遗传》2013年第1期62-72,共11页Hereditas（Beijing)

基　　金：国家重点基础研究发展计划项目(973计划)(编号:2004CCA02200);国家自然科学基金项目(编号:81070794);国家青年科学基金项目(编号:31100903);浙江省重大科技专项社会发展项目(编号:2007C13021);浙江省自然基金项目(编号:Y2110399),浙江省自然基金项目(编号:Y12H130007);浙江省卫生厅项目(编号:2009A135);浙江省研究生创新科研项目(编号:YK2010084);温州市瓯海区科技计划项目(编号:2011XM047)资助

摘　　要：线粒体12S rRNA A1555G突变是引起氨基糖甙类药物诱导的非综合征型耳聋的重要原因之一。文章对收集的25个携带A1555G突变的中国汉族非综合征型耳聋家系进行了临床和分子遗传学评估。结果表明,这25个家系的母系成员在耳聋外显率、听力损失严重程度和发病年龄上存在较大差异。当包括和不包括氨基糖甙类药物使用史时,耳聋的平均外显率分别为28.1%和21.5%,排除氨基糖甙类药物时,耳聋的平均发病年龄从1~15岁不等。线粒体全序列分析发现了16个新变异,不同的线粒体DNA多态性位点显示这25个家系分别属于东亚人群A、B、D、F、G、M、N和R单倍型,其中线粒体单倍型B的家系耳聋外显率和表现度较其他单倍型高。此外,7个继发突变位点和21个高保守性位点突变可能增加了这些家系的耳聋外显率。GJB2基因上未检测到与耳聋相关的突变,表明在本研究的耳聋家系中,GJB2基因可能没有参与A1555G突变的表型表达。以上各方面提示,线粒体单倍型和其他因素可能参与了这25个家系耳聋患者的表型修饰。Mitochondrial 12S rRNA A1555AG mutation is one of the important causes of aminoglycoside-induced and nonsyndromic deafness. We report here the cilinical, genetic and molecular characterization of 25 Chinese families carrying the A1555G mutation.Clinical and genetic characterizations of these Chinese families exhibited a wide range of penetrance, severity and age-at-onset of hearing impairment. The average penetrances of deafiaess were 28.1% and 21.5%, respectively,when aminoglycoside-induced hearing loss was included or excluded. Furthermore, the average age-of-onset for deafness without aminoglycoside exposure ranged from 1 and 15 years old. Their mitochondrial genomes exhibited distinct sets of polymorphisms including 16 novel variants, belonging to ten Eastern Asian haplogroups A, B, D, F, G,M, N and R, respectively. Strikingly, these Chinese families carrying mitochondrial haplogroup B exhibited higher penetrance and expressivity of hearing loss. In addition, 7 known secondary mutations and 21 variants resided at the highly conservative residues may enhance the penetrace of hearing loss in these Chinese families. Moreover, the absence of mutation in GJB2 gene suggested that GJB2 may not be a modifier for the phenotypic expression of the A1555G mutation in these Chinese families. These observations suggested that mitochondrial haplotypes and other modifiers may modulate the variable penetrance and expressivity of deafness among these Chinese families.

关 键 词：线粒体12S rRNA A1555G突变 非综合征型耳聋 氨基糖甙类抗生素 单倍型 

分 类 号：R764[医药卫生—耳鼻咽喉科]