Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders.
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.
Mollet
Julie
J
INSERM U781 and Department of Genetics, Hôpital Necker-Enfants Malades, Paris, France.
Giurgea
Irina
I
Schlemmer
Dimitri
D
Dallner
Gustav
G
Chretien
Dominique
D
Delahodde
Agnès
A
Bacq
Delphine
D
de Lonlay
Pascale
P
Munnich
Arnold
A
Rötig
Agnès
A
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
D003067:Coenzymes; D014451:Ubiquinone; D019883:Alkyl and Aryl Transferases; C021386:4-hydroxybenzoate polyprenyltransferase; C519259:prenyldiphosphate synthase, subunit 1, human; C024989:coenzyme Q10