Baertling Fabian, A M van den Brand Mariel, Hertecant Jozef L, Al-Shamsi Aisha, P van den Heuvel Lambert, Distelmaier Felix, Mayatepek Ertan, Smeitink Jan A, Nijtmans Leo G J, Rodenburg Richard J T
Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, GA Nijmegen, The Netherlands; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
Hum Mutat. 2015 Jan;36(1):34-8. doi: 10.1002/humu.22715. Epub 2014 Nov 18.
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.
COA6/C1ORF31参与细胞色素c氧化酶（复合体IV）的生物合成。我们报告了在一名患有新生儿肥厚型心肌病且存在孤立性复合体IV缺陷的患者中检测到的一种新的致病性COA6变异。首次给出了关于一名COA6缺陷患者的临床细节，并对患者成纤维细胞进行了功能表征：未检测到COA6蛋白，复合体IV及其几个亚基的稳态水平降低。单体COX1组装中间体积累。通过脉冲追踪实验，我们证明线粒体编码的复合体IV亚基的周转增加。尽管患者成纤维细胞中单体复合体IV减少，但CI/CIII2/CIVn超复合体不受影响。补充铜可部分挽救患者成纤维细胞中的复合体IV缺陷。我们得出结论，COA6是复合体IV亚基稳定性所必需的。此外，在向复合体IV亚基输送铜的途径中所提出的作用得到了证实，并为COA6缺陷患者提供了一种治疗线索。
