两个携带线粒体12S rRNA1494C〉T突变的耳聋家系的遗传学特征  

Characterization of two Chinese families with aminoglycoside-induced and nonsyndromic hearing loss both carrying a mitochondriai 12S rRNA 1494C〉T mutation

作　　者：龚莎莎[1] 陈波蓓 彭光华[3] 郑静[1] 张婷[1] 郑斌娇[1] 方芳[1] 张初琴 吕建新[1] 管敏鑫[1] 

机构地区：[1]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]附属第二医院耳鼻喉科 [3]浙江省余姚市人民医院耳鼻喉科

出　　处：《中华医学遗传学杂志》2012年第4期382-387,共6页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金（81070794）;国家“973”重大基础研究前期研究专项（2004CCA02200）;浙江省重大科技专项社会发展项目（2007C13021）;浙江省大学生科技成果推广项目

摘　　要：目的评估线粒体DNA继发突变、单倍型、GJB2基因等对1494C〉T突变表型的影响，进一步探讨母系遗传药物性耳聋和非综合征型耳聋的分子机制。方法收集2个携带1494C〉T突变的母系遗传药物性耳聋和非综合征型耳聋的中国家系，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。结果两个家系的母系成员在听力损失程度、发病年龄和听力曲线方面均存在较大差异，耳聋外显率（母系成员耳聋患者／所有母系成员）分别为42．9％和28．6％，非药物致聋的耳聋外显率（非药物性聋患者／所有母系成员）分别为14．3％和14．3％。两个家系分别属于东亚人群C4ala和B4blc单倍型。未在GJB2基因中发现与耳聋相关的致病位点。结论线粒体DNA1494C〉T突变为这两个家系的重要致病因素。氨基糖甙类抗生素可作为环境因素导致药物性耳聋的发生，GJB2基因的修饰作用可排除，而其他核修饰基因可能对这两个家系的表型具有修饰作用。携带1494C〉T突变的家系来自进化上不同的人群，其中属于单倍型B4blc的家系首次被发现，提示1494C〉T突变具有多起源性。Objective To evaluate the effect of mitochondrial DNA（mtDNA） secondary mutations, haplotypes, GJB2 gene mutations on phenotype of 1494C〉 T mutation, and to study the molecular pathogenic mechanism of maternally transmitted aminoglycoside-induced and nonsyndromic hearing loss. Methods Two Chinese Han pedigrees of maternally transmitted aminoglycoside induced and nonsyndromic hearing loss were collected. The two probands and their family members underwent clinical, genetic and molecular evaluations including audiological examinations and mutational analysis of mitochondrial genome and GJB2 gene. Results Clinical evaluation revealed wide range of severity, age-at-onset and audiometric configuration of hearing impairment in matrilineal relatives in both families, for which the penetrance of hearing loss was respectively 42.9% and 28.6% when aminoglycoside-induced deafness was included. When the effect of aminoglyeosides was excluded, the penetranees of hearing loss were 14. 3% and 14. 3%. Sequence analysis of mitochondrial genomes identified a known 12S rRNA 1494C〉T mutation, in addition with distinct sets of mtDNA polymorphisms belonging to Eastern Asian haplogroups C4ala and B4blc, respectively. Conclusion Mitochondrial 12S rRNA 1494C〉T mutation probably underlie the deafness in both families. Lack of significant mutation in the GJB2 gene ruled out involvement of GJB2 in the phenotypic expression. However, aminoglycosides and other nuclear modifier genes may still modify the phenotype of the 1494C〉T mutation in these families. The B4blc is a newly identified haplogroup in aminoglycoside- induced and nonsyndromic hearing loss family carrying the 1494C〉T mutation. The 1494C〉T mutation seems to have occurred sporadically through evolution.

关 键 词：氨基糖甙类抗生素 非综合征型耳聋 线粒体DNA 突变 单倍型 

分 类 号：R764[医药卫生—耳鼻咽喉科]