Jiang Pingping, Liang Min, Zhang Juanjuan, Gao Yinglong, He Zheyun, Yu Han, Zhao Fuxin, Ji Yanchun, Liu Xiaoling, Zhang Minglian, Fu Qun, Tong Yi, Sun Yanhong, Zhou Xiangtian, Huang Taosheng, Qu Jia, Guan Min-Xin
Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4778-88. doi: 10.1167/iovs.14-16158.
To investigate the prevalence and spectrum of mitochondrial ND4 mutations in subjects with Leber's hereditary optic neuropathy (LHON).
A cohort of 1281 Chinese Han probands and 478 control subjects underwent clinical and genetic evaluation, and sequence analysis of mitochondrial (mt) DNA, as well as enzymatic assay of NADH:ubiquinone oxidoreductase.
In this cohort, 503 probands had a family history of optic neuropathy and 778 subjects were sporadic cases. Mutational analysis of ND4 gene identified 149 (102 known and 47 novel) variants. The prevalence of known m.11778G>A mutation was 35.36%. Furthermore, we identified the known m.11696G>A and m.11253T>C mutations and five novel putative LHON-associated mutations. These mutations accounted for 2.74% of cases of LHON subjects. By enzymatic assay, we showed a mild decrease in the activity of NADH:ubiquinone oxidoreductase in mutant cell lines carrying only one putative mtDNA mutation. The low penetrance of optic neuropathy and mild biochemical defects in these pedigrees carrying only m.11696G>A mutation and one putative LHON-associated mutation suggested that the mutation(s) is(are) necessary but is(are) itself(themselves) insufficient to produce a visual failure. Moreover, mtDNAs in 169 probands carrying the LHON-associated mutation(s) were widely dispersed among 13 Eastern Asian haplogroups. In particular, the frequencies of haplogroups D, M8, M10, M11, and H in probands carrying the LHON-associated mtDNA mutation(s) were higher than those in Chinese controls.
These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON.
研究Leber遗传性视神经病变（LHON）患者中线粒体ND4突变的患病率及谱。
对1281名中国汉族先证者和478名对照者进行临床和基因评估、线粒体（mt）DNA序列分析以及NADH：泛醌氧化还原酶的酶活性测定。
在该队列中，503名先证者有视神经病变家族史，778名受试者为散发病例。ND4基因的突变分析鉴定出149个（102个已知和47个新的）变异。已知的m.11778G>A突变的患病率为35.36%。此外，我们鉴定出已知的m.11696G>A和m.11253T>C突变以及五个新的疑似与LHON相关的突变。这些突变占LHON患者病例的2.74%。通过酶活性测定，我们发现仅携带一个疑似mtDNA突变的突变细胞系中NADH：泛醌氧化还原酶的活性轻度降低。在仅携带m.11696G>A突变和一个疑似LHON相关突变的这些家系中，视神经病变的低外显率和轻度生化缺陷表明该突变是必要的，但本身不足以导致视力丧失。此外，携带LHON相关突变的169名先证者的mtDNA广泛分布于13个东亚单倍群中。特别是，携带LHON相关mtDNA突变的先证者中单倍群D、M8、M10、M11和H的频率高于中国对照组。
这些结果表明ND4基因是与LHON相关突变的热点。因此，这些发现可能为进一步了解LHON的致病机制提供有价值的信息。
