Mutations in COA6 cause Cytochrome c Oxidase Deficiency and Neonatal Hypertrophic Cardiomyopathy
Mutations in COA6 cause Cytochrome c Oxidase Deficiency and Neonatal Hypertrophic Cardiomyopathy
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DOI：
10.1002/humu.22715
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发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Rodenburg, Richard J. T.
中科院分区：
文献类型：
--
作者：
Baertling, Fabian;van den Brand, Mariel A. M.;Rodenburg, Richard J. T.
COA6/C1ORF31参与细胞色素C氧化酶(复合体IV)的生物发生。我们提出了一种在新生儿肥厚型心肌病和孤立的复合体IV缺乏症患者中发现的新的致病COA6变异体。首次给出了COA6缺乏症患者的临床细节，并对患者成纤维细胞进行了功能表征：COA6蛋白无法检测到，复合体IV及其几个亚单位的稳定水平降低。单体COX1组装中间体积累。利用脉冲追逐实验，我们证明了线粒体编码的复合体IV亚基的周转增加。虽然患者成纤维细胞中的单体复合体IV减少，但CI/CIII2/CIVn-超复合体不受影响。铜补充剂可部分挽救患者成纤维细胞中复杂的IV缺乏症。我们得出结论，COA6是复合体IV亚基稳定所必需的。此外，铜在铜转运途径中的作用得到证实，并为COA6缺乏症患者提供了治疗线索。
COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits. Although monomeric complex IV is decreased in patient fibroblasts, the CI/CIII2/CIVn-supercomplexes remain unaffected. Copper supplementation shows a partial rescue of complex IV deficiency in patient fibroblasts. We conclude that COA6 is required for complex IV subunit stability. Furthermore, the proposed role in the copper delivery pathway to complex IV subunits is substantiated and a therapeutic lead for COA6-deficient patients is provided.