title: Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.
abstract: Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.
authors.affiliation: Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece.
authors.forename: L C
authors.initials: LC
authors.lastname: Papadopoulou
authors.forename: C M
authors.initials: CM
authors.lastname: Sue
authors.forename: M M
authors.initials: MM
authors.lastname: Davidson
authors.forename: K
authors.initials: K
authors.lastname: Tanji
authors.forename: I
authors.initials: I
authors.lastname: Nishino
authors.forename: J E
authors.initials: JE
authors.lastname: Sadlock
authors.forename: S
authors.initials: S
authors.lastname: Krishna
authors.forename: W
authors.initials: W
authors.lastname: Walker
authors.forename: J
authors.initials: J
authors.lastname: Selby
authors.forename: D M
authors.initials: DM
authors.lastname: Glerum
authors.forename: R V
authors.initials: RV
authors.lastname: Coster
authors.forename: G
authors.initials: G
authors.lastname: Lyon
authors.forename: E
authors.initials: E
authors.lastname: Scalais
authors.forename: R
authors.initials: R
authors.lastname: Lebel
authors.forename: P
authors.initials: P
authors.lastname: Kaplan
authors.forename: S
authors.initials: S
authors.lastname: Shanske
authors.forename: D C
authors.initials: DC
authors.lastname: De Vivo
authors.forename: E
authors.initials: E
authors.lastname: Bonilla
authors.forename: M
authors.initials: M
authors.lastname: Hirano
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
authors.forename: E A
authors.initials: EA
authors.lastname: Schon
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins; D003001:Cloning, Molecular; D017124:Conserved Sequence / Q000235:genetics; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D030401:Cytochrome-c Oxidase Deficiency; D004252:DNA Mutational Analysis; D003576:Electron Transport Complex IV / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009468:Neuromuscular Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D002352:Carrier Proteins; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; D012333:RNA, Messenger; C498516:SCO2 protein, S cerevisiae; C400285:SCO2 protein, human; D029701:Saccharomyces cerevisiae Proteins; D003576:Electron Transport Complex IV; D003545:Cysteine