线粒体tRNAThr基因功能改变与Leber遗传性视神经病变的相关性研究

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that generally affects children to young adults with the rapid, painless, bilateral loss of central vision. Mutations in mitochondrial DNA (mtDNA) are the molecular basis for this disorder. Typical features in LHON pedigrees are marked variations in penetrance and gender bias among affected subjects. Matrilineal relatives within and among families, despite carrying the same LHON-associated mtDNA mutations, exhibited a wide range of severity, age-of-onset and penetrance of optic neuropathy. The primary LHON mutation is a prerequisite, but secondary factors such as secondary mutations, mitochondrial haplotypes, nuclear modifier genes and environmental factors are clearly modulating the risk of visual loss. However, these modifier factors remain poorly understood. To further elucidate the pathophysiology of LHON, we have made the molecular analysis of mitochondrial tRNAThr in 422 Chinese LHON subjects, and four LHON-associated candidate mtDNA mutations were found. In the present study, we will further investigate the molecular pathogenesis of these tRNAThr mutations. And these subjects underwent clinical, genetic evaluation and molecular analysis of mitochondrial tRNAThr. Genotypic spectrum of mitochondrial tRNAThr gene would be made. Through molecular genetics and cytobiology study of the four candidate mutations, understand the influence of mitochondriol dysfunction. After this study, we can understand the correlation of mtDNA mutations and LHON. Thus, our findings may provide new insights into pathophysiology of LHON.It may be important basis of diagnosis, therapy, precaution and genetic counseling.

Leber遗传性视神经病变（LHON）是一种典型的母系遗传病，主要累及青壮年男性，平均发病年龄为17-20岁，患者之间常呈现不同程度的视力损伤。研究表明线粒体DNA（mtDNA）突变是LHON发病的分子基础。本课题组前期已经对422个LHON家系进行线粒体tRNAThr突变筛查，并发现4个LHON相关的tRNAThr候选突变。本项目将在前期研究的基础上，绘制中国LHON人群线粒体tRNAThr突变频谱，并对4个LHON相关的tRNAThr突变进行分子遗传学和细胞生物学研究，明确线粒体tRNAThr突变对线粒体功能的影响，最终揭示线粒体tRNAThr突变导致的线粒体功能改变在LHON发病中的作用。本课题的完成将有助于深入理解mtDNA突变与LHON的关系，并为LHON的早期诊断、治疗、预防和遗传咨询提供理论依据，具有重要的社会价值。

Leber遗传性视神经病变（Leber's Hereditary Optic Neuropathy，LHON）（OMIM 535000）是一种主要累及视网膜神经节细胞及其轴索，导致视神经退行性变的母系遗传病（即母系后代发病而父系后代不发病）。青壮年男性好发，发病年龄常在17-20岁，患者可呈现1级、2级、3级到4级不同程度的视力损伤，病程可表现为视力突然完全丧失，也可呈渐进性下降。LHON呈母系遗传的特征，提示mtDNA突变为LHON发病的主要分子基础。本研究建立了一个包括DNA样本、永生淋巴细胞系、临床和遗传资料的LHON遗传资源库，进行线粒体tRNAThr基因的分子流行病学研究。通过对422个LHON家系进行线粒体tRNAThr基因突变筛查，绘制了中国LHON人群线粒体tRNAThr基因突变频谱；对tRNAThr m.15927G>A突变进行分子遗传学和细胞生物学研究，明确m.15927G>A突变对线粒体功能的影响，揭示m.15927G>A突变导致的线粒体功能改变在LHON发病中的作用。本课题的完成有助于深入理解线粒体tRNAThr基因突变与LHON的相关性，为LHON的早期诊断、治疗、预防和遗传咨询提供理论依据。