Kirby Denise M, Boneh Avihu, Chow C W, Ohtake Akira, Ryan Michael T, Thyagarajan Dominic, Thorburn David R
Murdoch Children's Research Institute, University of Melbourne, Victoria, Australia.
Ann Neurol. 2003 Oct;54(4):473-8. doi: 10.1002/ana.10687.
Respiratory chain complex I deficiency is a common cause of Leigh's disease (LD) and can be caused by mutations in genes encoded by either nuclear or mitochondrial DNA (mtDNA). Most pathogenic mtDNA mutations act recessively and only cause disease when present at high mutant loads (typically >90%) in tissues such as muscle and brain. Two mitochondrial DNA mutations in complex I subunit genes, G14459A in ND6, and T12706C in ND5, have been associated with complex I deficiency and LD. We report another ND5 mutation, G13513A, in three unrelated patients with complex I deficiency and LD. The G13513A mutation was present at mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. Blue Native polyacrylamide gel electrophoresis showed that fibroblasts with 45% G13513A mutant load had approximately 50% of the normal amount of fully assembled complex I. Fibroblasts with greater than 97% of the ND6 G14459A mutation had only 20% fully assembled complex I, suggesting that both mutations disrupt complex I assembly or turnover. We conclude that the G13513A mutation causes a complex I defect when present at unusually low mutant load and may act dominantly.
呼吸链复合体I缺乏是 Leigh 病（LD）的常见病因，可由核DNA或线粒体DNA（mtDNA）编码的基因突变引起。大多数致病性mtDNA突变呈隐性，只有在肌肉和大脑等组织中以高突变负荷（通常>90%）存在时才会导致疾病。复合体I亚基基因中的两个线粒体DNA突变，ND6中的G14459A和ND5中的T12706C，与复合体I缺乏和LD有关。我们报告了另一个ND5突变，G13513A，在三名患有复合体I缺乏和LD的无关患者中发现。在所有测试组织中，包括多个脑区，G13513A突变的突变负荷约为50%或更低。在培养细胞中导致复合体I缺陷的阈值突变负荷约为30%。蓝色天然聚丙烯酰胺凝胶电泳显示，G13513A突变负荷为45%的成纤维细胞具有正常量完全组装的复合体I的约50%。ND6 G14459A突变大于97%的成纤维细胞只有20%完全组装的复合体I，这表明这两种突变都破坏了复合体I的组装或周转。我们得出结论，G13513A突变在异常低的突变负荷下存在时会导致复合体I缺陷，并且可能起显性作用。
