title: Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders.
abstract: Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Deltacoq1 and Deltacoq2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.
authors.affiliation: INSERM U781 and Department of Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Mollet
authors.forename: Irina
authors.initials: I
authors.lastname: Giurgea
authors.forename: Dimitri
authors.initials: D
authors.lastname: Schlemmer
authors.forename: Gustav
authors.initials: G
authors.lastname: Dallner
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.forename: Agnès
authors.initials: A
authors.lastname: Delahodde
authors.forename: Delphine
authors.initials: D
authors.lastname: Bacq
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000293:Adolescent; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003067:Coenzymes; D005260:Female; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010085:Oxidative Phosphorylation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015003:Yeasts / Q000235:genetics
chemical_list: D003067:Coenzymes; D014451:Ubiquinone; D019883:Alkyl and Aryl Transferases; C021386:4-hydroxybenzoate polyprenyltransferase; C519259:prenyldiphosphate synthase, subunit 1, human; C024989:coenzyme Q10