title: Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.
abstract: 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.
authors.affiliation: 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.
authors.forename: Fabian
authors.initials: F
authors.lastname: Baertling
authors.forename: Mariel
authors.initials: M
authors.lastname: A M van den Brand
authors.forename: Jozef L
authors.initials: JL
authors.lastname: Hertecant
authors.forename: Aisha
authors.initials: A
authors.lastname: Al-Shamsi
authors.forename: Lambert
authors.initials: L
authors.lastname: P van den Heuvel
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.forename: Jan A
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Leo G J
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003300:Copper / Q000008:administration & dosage; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D008928:Mitochondria / Q000378:metabolism
chemical_list: D003300:Copper; D003576:Electron Transport Complex IV
keywords: C1ORF31; COA6; OXPHOS; cardiomyopathy; cytochrome c oxidase