遗传 ›› 2014, Vol. 36 ›› Issue (11): 1159-1167.doi: 10.3724/SP.J.1005.2014.1159

• 研究报告 • 上一篇    下一篇

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

刘莉1, 邵宇权2, 张宝荣3, 蒋萍萍1, 都爱莲3, 4, 管敏鑫1   

  1. 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
  • 收稿日期:2014-04-04 出版日期:2014-11-20 发布日期:2014-10-28
  • 通讯作者: 都爱莲,副主任医师,硕士生导师,研究方向:线粒体脑肌病的基础和临床研究。E-mail: lotusdu@126.com E-mail:21207041@zju.edu.cn
  • 作者简介:刘莉,硕士研究生,专业方向:遗传学。
  • 基金资助:
    国家自然科学基金项目(编号:81200967)资助

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

Li Liu1, Yuquan Shao2, Baorong Zhang3, Pingping Jiang1, Ailian Du3, 4, Minxin Guan1   

  1. 1. Institute of Genetics, College of Life Science, Zhejiang University, Hangzhou 310058, China;
    2. Department of Neurology, Sir Run Run Shao Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China;
    3. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China;
    4. Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
  • Received:2014-04-04 Online:2014-11-20 Published:2014-10-28

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。

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

Abstract: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a genetically heterogeneous disorder. The most prevalent mitochondrial DNA (mtDNA) mutation associated with MELAS is the m.3243A>G transition in the mitochondrial tRNALeu(UUR) gene. Here, we report the clinical, genetic and molecular characterization of six probands from Han Chinese families with MELAS. Four of six probands carried the heteroplasmic 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 diversity. Our finding also highlighted the complexity of the relationship between genotype and phenotype in MELAS.

Key words: mitochondrial DNA, MELAS, polymorphism, phenotype