The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy
The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy
复制标题
DOI：
10.1093/brain/124.1.209
复制
发表时间：
2001-01-01
期刊：
影响因子：
14.5
通讯作者：
Howell, N
中科院分区：
文献类型：
--
作者：
Chinnery, PF;Brown, DT;Howell, N
Leber遗传性视神经病变（LHON）是双侧视神经疾病的常见原因。大多数LHON患者携带线粒体DNA（mtDNA）复合物I或NADH：泛醌氧化还原酶（ND）基因的三个点突变之一（ND 4中的G11778A，ND 1中的G3460A，ND 6中的T14484C）。因此，筛查这些突变已成为对患有双侧视神经病变的年轻人进行常规临床研究的一部分，这些突变的缺失被解释为表明视神经病变为LHON的可能性很低。然而，有许多人发展LHON的临床特征，但没有这些主要LHON突变之一。我们描述了两个LHON家系，在mtDNA ND6基因（A14495G）内具有相同的新点突变。这种突变在两个家庭中都是异质性的，线粒体基因组测序证实了这种突变在两个独立的场合出现。这是导致视神经病变的ND6基因中的第七个突变，表明该基因是LHON突变的热点。蛋白质建模研究表明，所有这些致病突变都位于疏水裂缝或口袋中彼此非常接近。这是第一个证据之间的关系，一个特定的疾病表型和线粒体呼吸链亚基内的一个特定的结构域。这些研究结果表明，应对所有不携带三种常见LHON突变之一的LHON患者进行线粒体DNA ND 6基因测序。
Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease. The majority of LHON patients harbour one of three point mutations of the mitochondrial DNA (mtDNA) complex I, or NADH:ubiquinone oxidoreductase (ND) genes (G11778A in ND4, G3460A in ND1, T14484C in ND6). As a consequence, screening for these mutations has become part of the routine clinical investigation of young adults who present with bilateral optic neuropathy, and the absence of these mutations is interpreted as indicating there is a low likelihood that an optic neuropathy is LHON. However, there are many individuals who develop the clinical features of LHON but who do not harbour one of these primary LHON mutations. We describe two LHON pedigrees that harbour the same novel point mutation within the mtDNA ND6 gene (A14495G). This mutation was heteroplaslmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on two independent occasions. This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutations. Protein modelling studies indicate that all of these pathogenic mutations lie within close proximity to one another in a hydrophobic cleft or pocket. This is the first evidence for a relationship between a specific disease phenotype and a specific structural domain within a mitochondrial respiratory chain subunit. These findings suggest that the mtDNA ND6 gene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mutations.