线粒体tRNA^(Thr) G15927A突变可能影响耳聋相关的12S rRNA A1555G突变的表型表达  

Mitochondrial tRNA^(Thr) G15927A mutation may influence the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation

作　　者：唐霄雯[1] 李智渊[2] 吕建新[1] 朱翌[2] 李荣华 王金丹[1] 管敏鑫[1] 

机构地区：[1]温州医学院浙江省医学遗传学重点实验室,温州325035 [2]温州医学院附属第一医院耳鼻喉科,温州325000 [3]Division and Program in Human Genetic and Center for Hearing and Deafness Research,Cincinnati Children's Hospital Medical Cen-ter

出　　处：《遗传》2008年第10期1287-1294,共8页Hereditas（Beijing)

基　　金：国家重大基础研究前期研究专项(973项目)(编号:2004CCA02200);浙江省卫生厅课题(编号:2006A100);浙江省科技厅钱江人才优先资助项目(编号:2007G50G2090026);温州市科技局项目(编号:Y2006A031)资助~~

摘　　要：对1个中国汉族耳聋家系进行了临床和分子遗传学特征分析。家系中听力下降的母系成员表现为程度不等、听力图形态不同的听力损害,但同为双侧对称的感觉神经性耳聋。该家系耳聋外显率很高,包括药物致聋的耳聋外显率为75%,而非药物致聋的外显率为41.7%。对母系成员进行线粒体DNA(mtDNA)全序列扩增分析,发现了耳聋相关12SrRNAA1555G同质性突变位点和多态性位点,属于东亚人群B5b单体型。在这些变异位点中,mtDNA15927位点的G-A碱基变化破坏tRNAThr反密码子结构上十分保守的C-G碱基对,这可能加重由A1555G突变造成的线粒体功能缺陷。这表明tRNAThrG15927A突变可能增强携带12SrRNAA1555G的中国汉族耳聋家系的外显率和表现度。We report here the clinical and genetic evaluations as well as mutational analysis of mitochondrial DNA （mtDNA） in a four-generation Chinese Han family with aminoglycoside-induced and nonsyndromic hearing loss. Strikingly, this family exhibited a high penetrance and expressivity of hearing loss. The penetrances of hearing loss in this family were 75% and 41.7% respectively, when aminoglycoside-induced deafness was included or was excluded. The severity of hearing loss in matrilineal relatives varied from profound heating loss to normal hearing. Mutational analysis of mtDNA identified the homoplasmic A1555G mutation and a distinct set of mtDNA variants belonging to the Asian haplogroup B5b. Of these, the G15927A mutation absent in 156 Chinese controls is localized at the anticodon-stem of tRNATM at conventional position 42. The guanine at this position （G42） of tRNATh~ is highly conserved from bacteria to human mitochondria. Thus, it is antici- pated that the G15927A disrupted the highly conserved C-G base-pairing at the anticodon-stem of tRNArhr. The alteration of structure of this tRNA likely leads to a failure in tRNA metabolism, thereby worsens the mitochondrial dysfunction asso- ciated with the A1555G mutation. Thus, the G15927A mutation has a potential modifying role in increasing the penetrance and expressivity of hearing loss associated with the deafness-associated 12S rRNAA1555G mutation in this Chinese pedigree.

关 键 词：耳聋 线粒体DNA(mtDNA) 突变 单体型 tRNA 氨基糖甙类抗生素 

分 类 号：R764[医药卫生—耳鼻咽喉科]