2. Academic Validation
  3. Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive

Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive

  • Hum Mutat. 2017 Jun;38(6):692-703. doi: 10.1002/humu.23210.
Fabian Baertling 1 2,  Fathiya Al-Murshedi 3,  Laura Sánchez-Caballero 1,  Khalfan Al-Senaidi 4,  Niranjan P Joshi 4,  Hanka Venselaar 5,  Mariël Am van den Brand 1,  Leo Gj Nijtmans 1,  Richard Jt Rodenburg 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 2 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Düsseldorf, Germany.
  • 3 Genetic and Developmental Medicine Clinic, Department of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
  • 4 Pediatric Cardiology Unit, Department of Child Health, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
  • 5 Centre for Molecular and Biomolecular Informatics, Radboud University, Nijmegen, The Netherlands.
PMID: 28247525 DOI: 10.1002/humu.23210
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.

Keywords

COX5A; OXPHOS; complex IV; cytochrome c oxidase; pulmonary arterial hypertension.

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