title: Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature.
abstract: BACKGROUND
  We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature.
  
  
  RESULTS
  Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors.
  
  
  CONCLUSIONS
  The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergaard
authors.affiliation: Department of Human Genetics and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Woranontee
authors.initials: W
authors.lastname: Weraarpachai
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Ravn
authors.affiliation: Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Alfred Peter
authors.initials: AP
authors.lastname: Born
authors.affiliation: Department of Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.affiliation: Department of Human Genetics and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.affiliation: Department of Neurology and Neuromuscular Research Unit, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Vissing
mesh_terms: D000328:Adult; D002675:Child, Preschool; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics* / Q000473:pathology; D004392:Dwarfism / Q000235:genetics / Q000473:pathology; D003576:Electron Transport Complex IV / Q000235:genetics; D015444:Exercise / Q000502:physiology; D059472:Exome; D005260:Female; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000473:pathology
chemical_list: C578539:COA3 protein, human; C570605:COX14 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D003576:Electron Transport Complex IV
keywords: COA3; Complex IV; Mitochondrial; Neuropathy