title: A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.
abstract: Cytochrome c oxidase (COX) defects are found in a clinically and genetically heterogeneous group of mitochondrial disorders. To date, mutations in only two nuclear genes causing COX deficiency have been described. We report here a genetic linkage study of a consanguineous family with an isolated COX defect and subsequent identification of a mutation in a third nuclear gene causing a deficiency of the enzyme. A genome-wide search for homozygosity allowed us to map the disease gene to chromosome 17p13.1-q11.1 (Z (max)= 2.46; theta = 0.00 at the locus D17S799). This region encompasses two genes, SCO1 and COX10, encoding proteins involved in COX assembly. Mutation analysis followed by a complementation study in yeast permitted us to ascribe the COX deficiency to a homozygous missense mutation in the COX10 gene. This gene encodes heme A:farnesyltransferase, which catalyzes the first step in the conversion of protoheme to the heme A prosthetic groups of the enzyme. All three nuclear genes now linked to isolated COX deficiency are involved in the maturation and assembly of COX, emphasizing the major role of such genes in COX pathology.
authors.affiliation: INSERM U393, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Valnot
authors.forename: J C
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: A
authors.initials: A
authors.lastname: Barrientos
authors.forename: M
authors.initials: M
authors.lastname: Gorbatyuk
authors.forename: J W
authors.initials: JW
authors.lastname: Taanman
authors.forename: B
authors.initials: B
authors.lastname: Mehaye
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: A
authors.initials: A
authors.lastname: Tzagoloff
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: A
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D019943:Amino Acid Substitution; D001483:Base Sequence; D002675:Child, Preschool; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D003241:Consanguinity; D030401:Cytochrome-c Oxidase Deficiency; D004252:DNA Mutational Analysis; D017931:DNA Primers; D003576:Electron Transport Complex IV; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C490115:COX10 protein, human; D003576:Electron Transport Complex IV; D019883:Alkyl and Aryl Transferases; C086105:COX10 protein, S cerevisiae