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题名	中国Leber 氏遗传性视神经病人群mtDNA 突变和遗传背景影响发病的研究
作者	张阿梅
学位类别	博士
答辩日期	2010-11
授予单位	中国科学院研究生院
授予地点	北京
导师	姚永刚
关键词	LHON 线粒体DNA 单倍型类群
学位专业	细胞生物学
中文摘要	Leber氏遗传性视神经病（LHON）是最典型、最常见的线粒体遗传病之一，主要由三个线粒体DNA（mtDNA）原发突变（m.11778G>A、m.3460G>A和m.14484T>C）引起。患者主要表现为无痛性双侧视力下降或丧失，不完全外显和性别偏好是该病亟待解决的两大难题。LHON是研究线粒体疾病的极好模型，本文主要通过进化医学手段集中从mtDNA角度研究了我国LHON人群的致病突变和母系遗传背景。 我国LHON人群的临床外显率受mtDNA单倍型类群的影响，单倍型类群M7b1’2增加LHON原发突变m.11778G>A外显的风险，而M8a对该原发突变外显有保护效应，但这一临床关联分析结果没有在病例-对照研究中得到证实。为进一步分析LHON患者的母系遗传结构与发病的关系，我们对479个携带m.11778G>A的LHON患者和843个疑似LHON患者进行了mtDNA 控制区序列分析和单倍型类群的划分，并与1689个已报道的正常汉族人的母系遗传结构进行比较。发现疑似LHON患者的母系遗传结构与正常汉族人群一致，提示mtDNA遗传背景不影响疑似LHON患者的发病。携带m.11778G>A的LHON患者的母系遗传结构与正常人群或疑似LHON患者的遗传结构均有差异：单倍型类群R9，特别是其子类群F对携带m.11778G>A的LHON患者具有显著的保护作用，单倍型类群M7b和D4是LHON发病的危险因素。 除原发突变的mtDNA突变可影响LHON发病。m.1555A>G有增加LHON原发性突变m.11778G>A外显率的作用。稀有突变m.3635G>A是国人无三个原发突变LHON群体的发病原因之一。位于mt-tRNAphe的变异m.593T>C可能通过改变mt-tRNAphe的结构，进而影响线粒体蛋白合成过程，加重携带m.11778G>A LHON患者的发病。 总之，通过对我国携带m.11778G>A突变的LHON患者及疑似LHON患者进行mtDNA序列变异的系统分析，我们取得了一系列原创性结果，进一步证明了mtDNA的变异/突变可从多个方面影响LHON患者的发病。本研究为国人LHON病的遗传咨询和防治提供了理论基础和数据。
英文摘要	Leber’s hereditary optic neuropathy (LHON; MIM 535000) is one of the most typical and common mitochondrial diseases, with a manifestation of painless, acute or subacute bilateral visual loss in midlife. Over 95% LHON patients was caused by one of three primary mutations (m.11778G>A, m.3460G>A and m.14484T>C). Incomplete penetrance and gender bias are two riddles of this disease. LHON is the most suitable modle for studying the mitochondrial disorders. In this thesis, we mainly studied the influence of mtDNA variants and halogroup on Chinese LHON patients with m.11778G>A and on suspected patients who expressed LHON clinical features but lacking the three primary mutations. We sequenced the mtDNA control region sequences for all patients and determined the entire mtDNA genomes of some patients. Each sample was classified into respective haplogroup based on the haplogroup sequence motif. Our recent study has shown that mtDNA background could affect the clinical expression of LHON in Chinese. Haplogroup M7b1’2 could increase the risk of vision loss but haplogroup M8a might produce a protective effect. However, frequencies of haplogroups M7b1'2 and M8a are not significantly altered in LHON pedigrees despite their apparent background effect on the penetrance. We analyzed the matrilineal structure of 479 Chinese patients with m.11778G>A (sample #1) and of 843 suspected LHON patients (sample #2) in order to discern the mtDNA background effect on disease onset. Haplogroup distribution frequency in the patient group was compared to that of the general Han Chinese population (n=1,689; sample #3). The results showed that the matrilineal composition of the suspected LHON cohort resembles that of the general Han Chinese population, suggesting no association with mtDNA haplogroups. However, the LHON sample with m.11778G>A differs from the general Han Chinese and suspected LHON sample populations significantly by harboring fewer lineages belonging to haplogroup F (#1 vs. #2, P=9.133×10-23, OR=0.062; #1 vs. #3, P=1.999×10-24, OR=0.066) and more lineages belonging to M7b (#1 vs. #2, adjuseted P=0.047, OR=1.795; #1 vs. #3, adjusted P=0.018, OR=1.782) and D4 (#1 vs. #2, adjusted P=0.031, OR=1.628 and #1 vs. #3, P=0.085, OR=1.467). The mtDNA mutations could affect LHON onset. Co-occurrence of m.11778G>A and m.1555A>G in one LHON pedigree could increase LHON penetrance. The mutation m.3635G>A might be one of the rare pathogenic mutations in the LHON patients lacking the three primary mutaions. In addition, we observed an obviously higher frequency (2.92%, 14/479) of m.593T>C in the MT-TF gene in the LHON patients than in suspected LHON patients (1.42%, 12/843) or in general population (2.06%, 49/2374). We analyzed the conservation of m.593T>C, secondary structure prediction and in vitro transcription of the MT-TF gene. The results suggested that this variation changed the secondary structure of the MT-TF gene, further impaired synthetic ability of mitochondrial proteins, and involved in the onset of LHON with m.11778G>A. In summary, we analyzed the mtDNA variants and haplogroups in Chinese LHON patients with m.11778G>A and suspected LHON patients and identified that mtDNA variants/haplogroup can affect the onset of LHON. The results provided theoretical basis and data for genetic counselling and clinical prevention of LHON.
语种	中文
公开日期	2013-04-25
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/7409]
专题	昆明动物研究所_重大疾病机理的遗传学
推荐引用方式 GB/T 7714	张阿梅. 中国Leber 氏遗传性视神经病人群mtDNA 突变和遗传背景影响发病的研究[D]. 北京. 中国科学院研究生院. 2010.

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