title: CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures.
abstract: Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.
authors.affiliation: INSERM U781 and Department of Genetics, Hôpital Necker-Enfants Malades, Université René Descartes Paris V, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Mollet
authors.forename: Agnès
authors.initials: A
authors.lastname: Delahodde
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.forename: Dimitri
authors.initials: D
authors.lastname: Schlemmer
authors.forename: Anne
authors.initials: A
authors.lastname: Lombes
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Hélène Ogier
authors.initials: HO
authors.lastname: de Baulny
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D016227:Benzoquinones / Q000032:analysis; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002524:Cerebellar Ataxia / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry; D020125:Mutation, Missense; D010375:Pedigree; D012640:Seizures / Q000235:genetics*; D014451:Ubiquinone / Q000032:analysis / Q000172:deficiency* / Q000235:genetics
chemical_list: D016227:Benzoquinones; D014451:Ubiquinone; C004532:quinone; C030778:ubiquinone 8