Mutation of C20orf7 Disrupts Complex I Assembly and Causes Lethal Neonatal Mitochondrial Disease
Mutation of C20orf7 Disrupts Complex I Assembly and Causes Lethal Neonatal Mitochondrial Disease
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DOI：
10.1016/j.ajhg.2008.09.009
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发表时间：
2008-10-10
影响因子：
9.8
通讯作者：
Thorburn, David R.
中科院分区：
文献类型：
--
作者：
Sugiana, Canny;Pagliarini, David J.;Thorburn, David R.
复合物I（NADH：泛醌氧化还原酶）是线粒体呼吸链的第一个也是最大的多聚体复合物。人类复合物I包括由线粒体DNA编码的7个亚单位和38个核编码的亚单位，它们在一个仅部分理解的过程中组装在一起。迄今为止，已在所有14个核心亚基、5个额外亚基和4个组装因子中描述了引起复合物I缺陷的突变。我们描述了复合物I缺陷引起的突变的假定复合物I组装因子C20orf7。一个致命的新生儿形式的复合物I缺乏症的候选区域被确定的纯合性映射的一个埃及家庭与一个受影响的孩子和两个受影响的怀孕预测基于酶的产前诊断。通过微细胞介导的染色体转移证实了该区域，并对编码潜在线粒体蛋白的11个候选基因进行了测序。C20orf7纯合错义突变与家族疾病分离我们发现，C20orf7是周边与线粒体内膜的基质面，并沉默其表达与RNAi降低复合物I的活性。C20orf7患者成纤维细胞显示出几乎完全不存在复合物I全酶，并且在复合物I组装的所有早期阶段都有缺陷，但与组装因子NDUFAF1突变引起的组装缺陷不同。我们的研究结果表明，C20orf7是至关重要的组装复合物I和C20orf7的突变导致线粒体疾病。
Complex I (NADH:ubiquinone oxidoreductase) is the first and largest multimeric complex of the mitochondrial respiratory chain. Human complex I comprises seven Subunits encoded by mitochondrial DNA and 38 nuclear-encoded subunits that are assembled together in a process that is only partially understood. To date, Mutations causing complex I deficiency have been described in all 14 core subunits, five supernumerary Subunits, and four assembly factors. We describe complex I deficiency caused by mutation of the putative complex I assembly factor C20orf7. A candidate region for a lethal neonatal form of complex I deficiency was identified by homozygosity mapping of an Egyptian family with one affected child and two affected pregnancies predicted by enzyme-based prenatal diagnosis. The region was confirmed by microcell-mediated chromosome transfer, and 11 candidate genes encoding potential mitochondrial proteins were sequenced. A homozygous missense mutation in C20orf7 segregated with disease in the family. We show that C20orf7 is peripherally associated with the matrix face of the mitochondrial inner membrane and that silencing its expression with RNAi decreases complex I activity. C20orf7 patient fibroblasts showed an almost cornplete absence of complex I holoenzyme and were defective at all early stage of complex I assembly, but in a manner distinct from the assembly defects caused by mutations in the assembly factor NDUFAF1. Our results indicate that C20orf7 is crucial in the assembly of complex I and that mutations in C20orf7 cause mitochondrial disease.