细胞色素c氧化酶
生物
蛋白质亚单位
疾病基因鉴定
突变
分子生物学
表型
线粒体呼吸链
遗传学
外显子组测序
线粒体
基因
作者
Robert D S Pitceathly,Shamima Rahman,Yehani Wedatilake,James M. Polke,Sebahattin Çırak,A. Reghan Foley,Anna Sailer,Matthew E. Hurles,Jim Stalker,Iain P. Hargreaves,Cathy E. Woodward,Mary G. Sweeney,F. Muntoni,Henry Houlden,Jan‐Willem Taanman,Michael G. Hanna
出处
期刊:Cell Reports
[Elsevier]
日期:2013-06-01
卷期号:3 (6): 1795-1805
被引量:104
标识
DOI:10.1016/j.celrep.2013.05.005
摘要
The molecular basis of cytochrome c oxidase (COX, complex IV) deficiency remains genetically undetermined in many cases. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous pedigree with isolated COX deficiency linked to a Leigh syndrome neurological phenotype. Unexpectedly, affected individuals harbored homozygous splice donor site mutations in NDUFA4, a gene previously assigned to encode a mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase) subunit. Western blot analysis of denaturing gels and immunocytochemistry revealed undetectable steady-state NDUFA4 protein levels, indicating that the mutation causes a loss-of-function effect in the homozygous state. Analysis of one- and two-dimensional blue-native polyacrylamide gels confirmed an interaction between NDUFA4 and the COX enzyme complex in control muscle, whereas the COX enzyme complex without NDUFA4 was detectable with no abnormal subassemblies in patient muscle. These observations support recent work in cell lines suggesting that NDUFA4 is an additional COX subunit and demonstrate that NDUFA4 mutations cause human disease. Our findings support reassignment of the NDUFA4 protein to complex IV and suggest that patients with unexplained COX deficiency should be screened for NDUFA4 mutations.
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