中国Leber遗传性视神经病变G11696A突变两个家系分析

Leber＇s hereditary optic neuropathy is associated with the mitochondrial G11696A mutation in two Chinese families

目的对两个中国Leber遗传性视神经病变（Leber’s hereditary optic neuropathy，LHON）家系的临床和分子遗传学特征进行分析。方法眼科临床检查发现在这两个家系中只有先证者1人出现视力障碍，发病年龄分别为10岁和17岁。对这两个家系先证者使用24对有部分重叠的引物进行线粒体DNA（mitochondrial DNA，mtDNA）全序列扩增分析。结果没有发现mtDNA G11778A、G3460A和T14484C3个常见的突变位点，而发现了与LHON相关的NIM G11196A同质性突变位点的存在，在167名正常对照只发现1例G11696A突变。结论线粒体DNA全序列分析发现两个家系呈现独特的mtDNA多态性，都属于东亚单体型D4。不完全外显率和正常对照频率（1／167）表明G11696A突变本身不足以导致LHON的发生，说明其它因素在这两个LHON家系的表型表达中也起一定的作用。在这些家系mtDNA中缺乏影响重要功能突变位点的存在，排除了线粒体背景对LHON临床表型的影响。因此，核修饰基因、环境因素可能对两个中国G11696A突变家系的外显率和发病严重程度起促进作用。

Objective To report the clinical, genetic, and molecular characterization of two Chinese families with Leber＇ s hereditary optic neuropathy （LHON）. Methods Ophthalmological examinations showed that only probands in two families exhibited visual loss at the age of 10 and 17 years respectively. The entire mitochondrial genome of two probands was PCR amplified in 24 overlapping fragments using sets of oligonucleotide primers. Results Mutational analysis of mitochondrial DNA （mtDNA） in these pedigrees revealed the absence of three common LHON associated Gl1778A, G3460A and T144484 mutations but the presence of homoplastic LHON associated ND4 Gl1696A mutation, which was present in one out of 167 Chinese healthy controls. Conclusion Sequence analysis of the complete mitochondrial genomes in two pedigrees showed the distinct sets of mtDNA polymorphisms, belonging to Eastern Asian haplogroup D4. The incomplete penetrance of visual loss and the presence of one in 167 controls suggested that this mutation itself is insufficient to produce a clinical phenotype and other modifier factors play a role in the phenotypic manifestation. The lack of functional mtDNA variants in these pedigrees ruled out the role of mitochondrial background in the phenotypic expression of visual loss. Therefore, nuclear modifier gene（s） or environmental factor（s） may play a role in the phenotypic expression of the LHON-associated Gl1696A mutation in two Chinese pedigrees.