title: Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive.
abstract: COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.
authors.affiliation: Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Baertling
authors.affiliation: Genetic and Developmental Medicine Clinic, Department of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
authors.forename: Fathiya
authors.initials: F
authors.lastname: Al-Murshedi
authors.affiliation: Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez-Caballero
authors.affiliation: Pediatric Cardiology Unit, Department of Child Health, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
authors.forename: Khalfan
authors.initials: K
authors.lastname: Al-Senaidi
authors.affiliation: Pediatric Cardiology Unit, Department of Child Health, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
authors.forename: Niranjan P
authors.initials: NP
authors.lastname: Joshi
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University, Nijmegen, The Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mariël Am
authors.initials: MA
authors.lastname: van den Brand
authors.affiliation: Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Leo Gj
authors.initials: LG
authors.lastname: Nijtmans
authors.affiliation: Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Richard Jt
authors.initials: RJ
authors.lastname: Rodenburg
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000235:genetics*; D003574:Cytochrome c Group / Q000737:chemistry / Q000235:genetics*; D030401:Cytochrome-c Oxidase Deficiency; D003576:Electron Transport Complex IV; D005183:Failure to Thrive / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics; D009154:Mutation; D021122:Protein Subunits / Q000235:genetics
chemical_list: D003574:Cytochrome c Group; D021122:Protein Subunits; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; C576944:COX5A protein, human; D003576:Electron Transport Complex IV
keywords: COX5A; OXPHOS; complex IV; cytochrome c oxidase; pulmonary arterial hypertension