在中国科学院“百人计划”、国家杰出青年科学基金（30725044）资助下，中国科学院昆明动物研究所姚永刚课题组与中山大学中山眼科中心张清炯课题组通过合作研究，发现特定线粒体DNA（mtDNA）单倍型类群对Leber遗传性视神经病变（简称LHON）发病与否有重要影响，结果发表在生命科学领域国际顶尖杂志《美国人类遗传学杂志》（The American Journal of Human Genetics）（2007年影响因子11.092）。据悉，这是迄今我国学者在有关LHON与mtDNA相关研究方面，首次在这类顶尖杂志上发表论文。
LHON是导致青壮年突发双目失明的最常见眼病，也是最常见的线粒体基因遗传病，由德国医生Leber于1871年首先报告。1988年美国Wallace研究组首先确定LHON的病因，是由mtDNA突变所致，可以通过母亲传给全部后代。在我国上世纪九十年代，南京、福建和广州的学者相继发现我国LHON患者也是由mtDNA的几个常见原发突变所致。尽管LHON病因早已明确，但发病机制仍有三大难题不明：为什么mtDNA突变携带者只有不到三分之一发病？为什么男性发病率远远高于女性？为什么mtDNA突变携带者要在青壮年发病？这些有关发病风险问题的阐明，是本病预防、早期干预及治疗的关键。遗憾的是，国内部分同行误以为找到LHON的病因后就没有多少值得研究的了，并不支持基于这些关键问题的研究。
姚永刚课题组与张清炯课题组及其合作者首先从1600多个LHON家系中选择有m.11778G>A原发突变的家系，然后对175个有详细家系资料的家系进行了系统的分析。通过分析每个家系mtDNA不同区域变异类型来确定该mtDNA所属类群，结合每个家系中LHON发病情况进行回归分析，发现线粒体单倍型类群M7b1’2显著增加LHON的发病外显率，而单倍型类群M8a显著降低发病率。在对归属于上述单倍型类群的患者线粒体全基因组序列进行系统发育分析后发现，类群M7b1’2的致病性风险很可能是由于ND5基因上的类群特有性变异（m.12811T>C）和原发性突变之间存在的协同效应引发；相反，类群M8a含有的位于ATPase6基因上的两个类群特异性变异m.8584G>A和m.8684C>T很可能提供一种保护作用，阻止原发突变m.11778G>A的外显，进一步对含有这两个M8a特有变异的ATPase6蛋白二级结构变化的预测结果支持上述推测。该研究是目前东亚人群LHON病发情况和线粒体遗传背景之间关系的首次系统性研究，结果不仅对揭示mtDNA原发突变携带者LHON发病与否的相关危险因素有重要价值，而且为进一步阐明LHON复杂的发病机制等后续研究提供了很好的思路和基础，同时对国人LHON发病的遗传咨询和可能的早期干预提供了重要线索。（生物谷Bioon.com）
生物谷推荐原始出处：
The American Journal of Human Genetics，Volume 83, Issue 6, 760-768，Yanli Ji，Yong-Gang Yao
Mitochondrial DNA Haplogroups M7b1′2 and M8a Affect Clinical Expression of Leber Hereditary Optic Neuropathy in Chinese Families with the m.11778G→A Mutation
Yanli Ji1, 6, A-Mei Zhang2, 4, 6, Xiaoyun Jia1, Ya-Ping Zhang3, Xueshan Xiao1, Shiqiang Li1, Xiangming Guo1, Hans-Jürgen Bandelt5, Qingjiong Zhang1, 6 and Yong-Gang Yao2, 6, ,
1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
2 Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
3 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
4 Graduate School of Chinese Academy of Sciences, Beijing 100039, China
5 Department of Mathematics, University of Hamburg, Hamburg 20146, Germany
6 These authors contributed equally to this work
Abstract
Leber hereditary optic neuropathy (LHON) is the most extensively studied mitochondrial disease, with the majority of the cases being caused by one of three primary mitochondrial DNA (mtDNA) mutations. Incomplete disease penetrance and gender bias are two features of LHON and indicate involvement of additional genetic or environmental factors in the pathogenesis of the disorder. Haplogroups J, K, and H have been shown to influence the clinical expression of LHON in subjects harboring primary mutations in European families. However, whether mtDNA haplogroups would affect the penetrance of LHON in East Asian families has not been evaluated yet. By studying the penetrance of LHON in 1859 individuals from 182 Chinese families (including one from Cambodia) with the m.11778G→A mutation, we found that haplogroup M7b1′2 significantly increases the risk of visual loss, whereas M8a has a protective effect. Analyses of the complete mtDNA sequences from LHON families with m.11778G→A narrow the association of disease expression to m.12811T→C (Y159H) in the NADH dehydrogenase 5 gene (MT-ND5) in haplogroup M7b1′2 and suggest that the specific combination of amino acid changes (A20T-T53I) in the ATP synthase 6 protein (MT-ATP6) caused by m.8584G→A and m.8684C→T might account for the beneficial background effect of M8a. Protein secondary-structure prediction for the MT-ATP6 with the two M8a-specific amino acid changes further supported our inferences. These findings will assist in further understanding the pathogenesis of LHON and guide future genetic counseling in East Asian patients with m.11778G→A.
