Leber's hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families
Leber's hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families
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同质ND1 m.3635G > 9个汉族家系突变引起的Leber遗传性视神经病
DOI：
10.1016/j.mito.2014.08.008
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发表时间：
2014-09-01
期刊：
影响因子：
4.4
通讯作者：
Guan, Min-Xin
中科院分区：
文献类型：
--
作者：
Zhang, Juanjuan;Jiang, Pingping;Guan, Min-Xin
在这份报告中，我们研究了Leber遗传性视神经病变（LHON）相关的线粒体m.3635G>A（p.S110N，ND 1）突变的分子机制。对1070例汉族人进行ND 1基因突变筛查，发现9个母系遗传的LHON家系存在m.3635G>A突变。38（22男/16女）的162母系亲属在这些家庭表现出不同的严重程度和发病年龄的视神经病变。对他们的线粒体基因组的分子分析鉴定了同质m.3635G>A突变和不同的多态性集合，分别属于亚洲单倍群G2 a1、R11 a、D4、R11 a、M7 b2、G1 a、F1 a1、B4和N9 a3。使用通过将来自一个中国家族的淋巴母细胞系的线粒体转移到无mtDNA（rho（0））细胞中构建的胞质杂交体，我们发现与对照胞质杂交体相比，携带m.3635G>A突变的突变胞质杂交体中的NADH：泛醌氧化还原酶（复合物I）的活性降低了27%。由m.3635G>A突变引起的呼吸缺陷导致线粒体ATP合成效率降低。这些线粒体功能障碍导致突变胞质杂种中活性氧产生增加。这些数据为m.3635G>A突变导致LHON提供了直接证据。我们的研究结果可能为LHON的病理生理学的理解提供新的见解。(C)2014 Elsevier B. V.和线粒体研究学会。All rights reserved.
In this report, we investigated the molecular mechanism underlying Leber's hereditary optic neuropathy (LHON)-associated mitochondrial m.3635G>A (p.S110N, ND1) mutation. A mutational screening of ND1 gene in a cohort of 1070 Han Chinese subjects LHON identified the m.3635G>A mutation in nine Chinese families with suggestively maternally transmitted LHON. Thirty-eight (22 males/16 females) of 162 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. Molecular analysis of their mitochondria(genomes identified the homoplasmic m.3635G>A mutation and distinct sets of polymorphisms belonging to the Asian haplogroups G2a1, R11a, D4, R11a, M7b2, G1a, F1a1, B4, and N9a3, respectively. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from one Chinese family into mtDNA-less (rho(0)) cells, we showed similar to 27% decrease in the activity of NADH:ubiquinone oxidoreductase (complex I) in mutant cybrids carrying the m.3635G>A mutation, compared with control cybrids. The respiratory deficiency caused by the m.3635G>A mutation results in decreased efficiency of mitochondrial ATP synthesis. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cybrids. The data provide the direct evidence for the m.3635G>A mutation leading to LHON. Our findings may provide new insights into the understanding of pathophysiology of LHON. (C) 2014 Elsevier B.V. and Mitochondria Research Society. All rights reserved.