仅女性发病的Leber遗传性视神经病变家系的表型分析

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摘要目的：对仅有女性发病的11个携带m.11778G＞A突变的Leber遗传性视神经病变（LHON）家系中患者的表型表现进行分析。方法：对1 362例汉族LHON患者的MT-ND4基因进行了系统的筛查，再对携带MT-ND4 11778G＞A突变的11个家系进行线粒体全基因组测序及线粒体单体型分析。结果：筛查发现11个携带m.11778G＞A突变的LHON家系仅累及女性母系成员。此11个家系中患者LHON外显率较低，分别为16.7%、18.8%、15.0%、6.7%、6.7%、33.3%、20.0%、16.7%、7.7%、8.3%、25.0%，平均每个家系外显率为15.90%±0.08%。LHON患者的视力损伤程度由轻度到重度不等，发病年龄7～25（12.4±4.8）岁，属于LHON的高发年龄阶段。11位先证者的线粒体单体型分别为B5a、Z、N9、B4c1b、G2h、B5a、M7b、N9a10、C7b、M7b1、M10。结论：本研究中11个携带相同m.11778G＞A突变的不同家系之间，及在相同线粒体遗传背景下的同一家系中不同母系成员间LHON外显率和发病年龄都存在着显著差异，表明m.11778G＞A突变是LHON发病的分子基础，但突变本身并不足以造成LHON的表型表达，提示其他修饰因子（线粒体单体型、核修饰基因及环境因素）在LHON的发生发展中发挥了一定的作用。

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关键词 ： Leber遗传性视神经病变, 母系遗传, 线粒体, 外显率, 线粒体单体型

Abstract：Objective: Phenotypic performance of 11 Leber’s hereditary optic neuropathy (LHON) pedigrees carrying m.11778G>A mutations, who had only female-onset, was analyzed. Methods: In this study we systematically screened, the MT-ND4 gene of 1 362 patients of the Chinese Han nationality with LHON. Mitochondrial genome sequencing and mitochondrial haplotype analysis were performed on 11 pedigrees carrying MT-ND4 m.11778G>A mutation. Results: Screening revealed that 11 cases of LHON pedigrees carrying m.11778G>A mutation only affected female maternal members. The LHON penetrance rate of these pedigrees showed low level, with 16.7%, 18.8%, 15.0%, 6.7%, 6.7%, 33.3%, 20.0%, 16.7%, 7.7%, 8.3%, 25.0% respectively. The average penetrance rate of each pedigree was 15.90%±0.08%. The degree of visual impairment in patients with LHON varied from mild to severe. The age of onset ranged from 7 to 25 years old. The average age of onset was (12.4±4.8) years old, being the high-risk age of LHON. The mitochondrial haplotype of 11 proband were B5a, Z, N9, B4c1b, G2h, B5a, M7b, N9a10, C7b, M7b1, M10 respectively. Conclusion: In this article, there were significant differences in LHON penetrance and age of onset between 11 different pedigrees with the same m.11778G>A mutation and different maternal members in the same mitochondrial genetic background. This suggests that m.11778G>A mutation is the molecular basis of the pathogenesis of LHON, but the mutation itself is not sufficient to induce the phenotypic expression of LHON, suggesting that other modification factors (mitochondrial haplotypes, nuclear modifier genes and environmental factors) may play a role in the development of LHON.

Key words： Leber’s hereditary optic neuropathy maternal inheritance mitochondria penetrance mitochon-drial haplotype

收稿日期: 2019-02-19

基金资助:国家自然科学基金资助项目（81200724）。

通讯作者: 管敏鑫，教授，Email：gminxin88@gmail.com。

作者简介: 吕媛媛（1994-），女，浙江衢州人，硕士生。

链接本文:

https://xb.wmu.edu.cn/CN/ 或 https://xb.wmu.edu.cn/CN/Y2019/V49/I7/475

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