6个线粒体脑肌病伴高乳酸血症和卒中样发作综合征(MELAS)家系先证者线粒体基因全序列比较分析  

Mitochondrial genome analysis in the probands of six Chinese families with MELAS

作　　者：刘莉[1] 邵宇权[2] 张宝荣[3] 蒋萍萍[1] 都爱莲[3,4] 管敏鑫[1] 

机构地区：[1]浙江大学生命科学学院遗传学研究所,杭州310058 [2]浙江大学医学院附属邵逸夫医院神经内科,杭州310016 [3]浙江大学医学院附属第二医院神经内科,杭州310009 [4]上海交通大学医学院附属同仁医院神经内科,上海200336

出　　处：《遗传》2014年第11期1159-1167,共9页Hereditas（Beijing)

基　　金：国家自然科学基金项目(编号:81200967)资助

摘　　要：线粒体脑肌病伴高乳酸血症和卒中样发作综合征（Mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes,MELAS）是一种异质性很强的遗传代谢性疾病,而位于tRNA Leu（UUR）基因的A3243G突变是该疾病最常见的致病位点.文章对6个汉族MELAS家系的先证者进行了临床病理、分子遗传学特征分析,探讨了线粒体基因多态性对MELAS病人表型可能产生的影响.线粒体基因检测结果显示,4例先证者为A3243G阳性,其异质性比例介于29％～59％之间,临床症状的严重性和异质性程度大致呈正相关;2例MELAS/Leigh叠加综合征先证者为A3243G阴性,复发次数和严重程度重于其他4例先证者,其中1例先证者的血液和肌肉组织中发现ND5基因T13094C突变,该位点已报道与MELAS/Leigh叠加综合征、小脑共济失调相关.另外,线粒体基因全序列测序结果显示：除主要致病突变外,还存在多个与耳聋、癫痫、糖尿病、心肌病、Leigh综合征相关的线粒体基因多态位点,临床症状严重的患者其多态位点也更多.这表明MELAS综合征的复杂表型不仅受致病突变位点的直接影响,也可能受到其他与疾病相关的多态性位点的修饰作用.Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes （MELAS） is a geneticallyheterogeneous disorder. The most prevalent mitochondrial DNA （mtDNA） mutation associated with MELAS is the m.3243A〉G transition in the mitochondrial tRNA^Leu（uuR） gene. Here, we report the clinical, genetic and molecu- lar characterization of six probands from Han Chinese families with MELAS. Four of six probands carried the hete- roplasmic m.3243A〉G mutation. The levels of mutation load ranged from 29% to 59%, which were correlated with the severity of the clinical phenotypes. Two probands with MELAS/Leigh overlap were 3243 A〉G negative, whose severity and relapse were greater than the other 4 probands. One proband with MELAS/Leigh harbored the known ND5 m.13094T〉C mutation, which is related to MELAS/Leigh overlap and cerebella ataxia. Sequence analysis of entire mtDNA showed the distinct sets of variants including some variants that may be associated with diabetes, hearing loss, seizures, cardiomyopathy, and Leigh syndrome. Our data suggested that the phenotype and severity of MELAS mainly depend on the mutation load, and some variants may partially contribute to the phenotype and diver- sity. Our finding also highlighted the complexity of the relationship between genotype and phenotype in MELAS.

关 键 词：线粒体基因 线粒体脑肌病伴高乳酸血症和卒中样发作综合征 多态性 表型 

分 类 号：R742[医药卫生—神经病学与精神病学]