Mutations inCOA6cause CytochromecOxidase Deficiency and Neonatal Hypertrophic Cardiomyopathy

• DOI: 10.1002/humu.22715
• Publication Date: 2014-10-22T09:19:53Z
• Authors: Fabian Baertling; Mariel A.M. van d...; Jozef L. Hertecant; Aisha Al-Shamsi; Lambert P. van de...; Felix Distelmaier; Ertan Mayatepek; Jan A. Smeitink; Leo G.J. Nijtmans; Richard J.T. Rode...
• Keywords: 0301 basic medicine; Infant, Newborn; Cytochrome-c Oxidase Deficiency; Cardiomyopathy, Hypertrophic; Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences; Mitochondria; 3. Good health; Electron Transport Complex IV; 03 medical and health sciences; HEK293 Cells; Humans; Female; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences; Copper

COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about COA6-deficient are given fibroblasts functionally characterized: protein undetectable steady-state levels of several its subunits reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover mitochondrial encoded subunits. Although decreased fibroblasts, CI/CIII2 /CIVn -supercomplexes remain unaffected. Copper supplementation shows partial rescue deficiency fibroblasts. conclude that required for subunit stability. Furthermore, proposed role copper delivery pathway to substantiated therapeutic lead patients provided.