A Mutation in C2orf64 Causes Impaired Cytochrome c Oxidase Assembly and Mitochondrial Cardiomyopathy
A Mutation in C2orf64 Causes Impaired Cytochrome c Oxidase Assembly and Mitochondrial Cardiomyopathy
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DOI：
10.1016/j.ajhg.2011.03.002
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发表时间：
2011-04-08
影响因子：
9.8
通讯作者：
Rodenburg, Richard J. T.
中科院分区：
文献类型：
--
作者：
Huigsloot, Merei;Nijtmans, Leo G.;Rodenburg, Richard J. T.
线粒体呼吸链复合物IV（细胞色素c氧化酶）的组装涉及几种组装分子伴侣的协调作用。在酿酒酵母中，已经鉴定了至少30种不同的组装分子伴侣。迄今为止，导致线粒体疾病的致病性突变仅在7个相应的人类基因中被发现。与人类病理学相关性未知的基因之一是C2 orf 64，它是S.酿酒酵母基因PET 191。该基因先前已被证明是酵母中的复杂IV装配因子，尽管其确切作用仍不清楚。先前在一个大的复合物IV缺乏症患者队列中的研究不支持C2 orf 64在复合物IV缺乏症中的病因作用。在这份报告中，C2 orf 64纯合突变被描述在两个兄弟姐妹的致命新生儿心肌病的影响。突变的致病性得到互补实验结果的支持，该结果表明，在患者来源的成纤维细胞中，通过野生型C2 orf 64的逆转录病毒转导可以完全恢复复合物IV的活性。通过2D-BN PAGE对患者成纤维细胞中复合物IV组装中间体的详细分析揭示了含有亚基COX 1但不含COX 2、COX 4或COX 5 b亚基的小组装中间体的积累，表明C2 orf 64参与了复合物IV组装过程的早期步骤。这项研究的结果表明，C2 orf 64是必不可少的人类复杂的IV大会和C2 orf 64突变分析应考虑复杂的IV缺陷的患者，特别是那些与肥厚型心肌病。
The assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase) involves the coordinated action of several assembly chaperones. In Saccharomyces cerevisiae, at least 30 different assembly chaperones have been identified. To date, pathogenic mutations leading to a mitochondrial disorder have been identified in only seven of the corresponding human genes. One of the genes for which the relevance to human pathology is unknown is C2orf64, an ortholog of the S. cerevisiae gene PET191. This gene has previously been shown to be a complex IV assembly factor in yeast, although its exact role is still unknown. Previous research in a large cohort of complex IV deficient patients did not support an etiological role of C2orf64 in complex IV deficiency. In this report, a homozygous mutation in C2orf64 is described in two siblings affected by fatal neonatal cardiomyopathy. Pathogenicity of the mutation is supported by the results of a complementation experiment, showing that complex IV activity can be fully restored by retroviral transduction of wild-type C2orf64 in patient-derived fibroblasts. Detailed analysis of complex IV assembly intermediates in patient fibroblasts by 2D-BN PAGE revealed the accumulation of a small assembly intermediate containing subunit COX1 but not the COX2, COX4, or COX5b subunits, indicating that C2orf64 is involved in an early step of the complex IV assembly process. The results of this study demonstrate that C2orf64 is essential for human complex IV assembly and that C2orf64 mutational analysis should be considered for complex IV deficient patients, in particular those with hypertrophic cardiomyopathy.