Mitochondrial ND1 Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy
Mitochondrial ND1 Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy
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1281 名患有 Leber 遗传性视神经病的中国受试者中的线粒体 ND1 变异
DOI：
10.1167/iovs.16-19243
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发表时间：
2016-05-01
影响因子：
4.4
通讯作者：
Guan, Min-Xin
中科院分区：
文献类型：
--
作者：
Ji, Yanchun;Liang, Min;Guan, Min-Xin
目的.本研究旨在探讨Leber遗传性视神经病变（Leber's hereditary optic neuropathy，LHON）患者线粒体ND1基因突变的发生率及突变谱。对1281名汉族先证者和478名对照者进行了线粒体（mt）DNA序列分析。所得的变体进行了评估的进化保守性，等位基因频率，结构和功能的后果。使用来自25个携带mtDNA突变的先证者和3个对照的淋巴母细胞系测量呼吸复合物活性。突变分析确定了MTND1基因中的178个（70个错义和108个沉默）变体。已知M的发生率。3460G> A，m. 3635G> A，m. 3733G> A，m. 3866T> C和m. 3394 T> C突变分别为1.33%、0.86%、0.08%、0.55%和2.97%。在27名先证者中发现了15种新的推定突变，占该队列病例的2.1%。复合物I在携带一个推定突变的突变细胞系中的活性范围为对照细胞系中的平均值的66%至76%，而复合物II、III和IV在突变细胞中的活性与对照中的活性相当。在携带新型推定突变的谱系中观察到视神经病变的低渗透率。101例MT-ND1突变先证者的mtDNA分布在15个东亚单倍群中。特别是携带ND1突变的患者中单倍群M、M9和M10的出现率高于对照组。这些数据表明MT-ND1基因是LHON相关突变的热点。本研究结果可为LHON的病理生理学、治疗及遗传咨询提供有价值的信息。
PURPOSE. The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON).METHODS. A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt) DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls.RESULTS. Mutational analysis identified 178 (70 missense and 108 silent) variants in the MTND1 gene. The incidences of known m. 3460G>A, m. 3635G>A, m. 3733G>A, m. 3866T>C, and m. 3394T> C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls.CONCLUSIONS. These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON.