线粒体单倍型对Leber病的影响

The influence of mitochondrial haplogroup on Leber＇ s hereditary optic neuropathy

在Leber遗传性视神经病变（Leber＇ s hereditary optic neuropathy, LHON）家系中由母系传递这种视觉功能障碍，提示线粒体基因组（mitochondrial DNA, mtDNA）突变为该疾病发生的主要分子基础。在不同种族人群的LHON家系中，有50％以上是由于mtDNA编码呼吸链复合体Ⅰ上ND1 G4360A, ND4 G11778A 和ND6 T14484C突变引起的。这3个突变位点因为致病率高，被称为原发性突变。但是携带这些位点突变的母系成员并不是都会出现LHON症状，而且在同一个家系内或不同家系间携带相同mtDNA突变的患者在发病年龄、视力损伤程度和发病过程也都不完全一样。这提示可能这些LHON相关的原发性突变本身不足以导致临床表现。LHON的男性多发、不完全外显和不同的基因表现度表明还有其他因素在疾病的发生发展过程起到修饰作用，这些因素包括：个人因素、环境因素、核修饰基因和mtDNA单倍型。特别是mtDNA单倍型，在对携带3个LHON相关原发性突变的家系中母系成员的发病起到协同作用。

Leber＇ s hereditary optic neuropathy （LHON） is a maternally inherited disorder leading to rapid, painless, bilateral and usually permanent central vision loss in young adults, males are preferentially affected. The maternal transmission of this visual dysfunction in LHON families suggested that mutations in the mitochondrial DNA （mtDNA） are the molecular bases of the disorder. The ND1 G3460A, NIM Gl1778A and ND6 T14484C mutations in the genes encoding the subunits of respiratory chain complex 1, account for more than 50% of LHON families worldwide. These three mutations are designated to be primary mutations because they impart a high risk for LHON expression. However, matrilineal relatives within and among families, despite carrying the same LHON-associated mtDNA mutation（s）, exhibit a wide range of onset, severity, and the progression of visual impairment. These findings strongly indicated that the LHON-associated primary mutation（s） are the primary factors underlying the development of vision loss, but they themselves are insufficient to produce a clinic phenotype. The prone to male, incomplete penetrance, and phenotypic variability of vision loss suggest that other modifier factors including personal factors, environmental factors, nuclear mod- i_tier genes and mitochondrial haplotypes contribute to the phenotypic expression of these mtDNA mutations. In particular, the mitochondrial haplotypes may play a synergic role in the development of vision loss in the families carrying the LHON- associated primary mtDNA mutation（s）.