Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency
Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency
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DOI：
10.1093/hmg/9.5.795
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发表时间：
2000-03-22
影响因子：
3.5
通讯作者：
Shoubridge, EA
中科院分区：
文献类型：
--
作者：
Jaksch, M;Ogilvie, I;Shoubridge, EA
位于22号染色体上的细胞色素c氧化酶(COX)装配基因SCO2的突变最近被报道在致死性婴幼儿心脑肌病和严重的心肌和骨骼肌COX缺乏症患者中。SCO2蛋白被认为是一种铜伴侣蛋白。为了研究SCO2突变在多大程度上导致这种表型，对9个家系的10名患者进行了该基因的完整序列分析。在两个无血缘关系的家系中的三名患者中发现了SCO2突变。我们检测到两个错义突变，其中一个(G1541A)导致高度保守的CxxxC金属结合位点附近的E140K替换。另一个(C1634T)导致R171W取代距离铜结合位更远。在表现为快速进行性致死性心脑肌病的两个兄弟姐妹中，在一个等位基因上发现了一个无意义密码子。有趣的是，到目前为止报道的所有患者都是G1541A突变的复合杂合子，这表明这要么是一个古老的等位基因，要么是一个突变热点。患者成纤维细胞中的COX缺陷(-50%)不会导致COX复合体多肽亚单位的稳态水平显著下降，可以通过转移22号染色体来挽救，但不能转移其他染色体。这些数据表明，SCO2的突变导致了一种以肥厚性心肌病和脑病为特征的致命的婴儿线粒体疾病，并表明在这种临床表型中存在一个或多个其他基因，可能在铜的输送途径中。
Mutations in SCO2, a cytochrome c oxidase (COX) assembly gene located on chromosome 22, have recently been reported in patients with fatal infantile cardioencephalomyopathy and severe COX deficiency in heart and skeletal muscle. The Sco2 protein is thought to function as a copper chaperone. To investigate the extent to which mutations in SCO2 are responsible for this phenotype, a complete sequence analysis of the gene was performed on ten patients in nine families. Mutations in SCO2 were found in three patients in two unrelated families. We detected two missense mutations, one of which (G1541A) results in an E140K substitution adjacent to the highly conserved CxxxC metal-binding site. The other (C1634T) results in an R171W substitution more distant from the copper-binding site. A nonsense codon was found on one allele in two siblings presenting with a rapidly progressive fatal cardioencephalomyopathy. Interestingly, all patients so far reported are compound heterozygotes for the G1541A mutation, suggesting that this is either an ancient allele or a mutational hotspot. The COX deficiency in patient fibroblasts (-50%) did not result in a measurable decrease in the steady-state levels of COX complex polypeptide subunits and could be rescued by transferring chromosome 22, but not other chromosomes. These data indicate that mutations in SCO2 cause a fatal infantile mitochondrial disorder characterized by hypertrophic cardiomyopathy and encephalopathy, and point to the presence of one or more other genes, perhaps in the copper delivery pathway, in this clinical phenotype.