title: Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients.
abstract: We have studied the fibroblasts of three patients suffering from Leigh syndrome associated with cytochrome c oxidase deficiency (LS-COX-). Their mitochondrial DNA was functional and all nuclear COX subunits had a normal sequence. The expression of transcripts encoding mitochondrial and nuclear COX subunits was normal or slightly increased. Similarly, the OXA1 transcript coding for a protein involved in COX assembly was increased. However, several COX-protein subunits were severely depressed, indicating deficient COX assembly. Surf1, a factor involved in COX biogenesis, was recently reported as mutated in LS-COX- patients, all mutations predicting a truncated protein. Sequence analysis of SURF1 gene in our three patients revealed seven heterozygous mutations, six of which were new : an insertion, a nonsense mutation, a splicing mutation of intron 7 in addition to three missense mutations. The mutation G385 A (Gly124-->Glu) changes a Gly that is strictly conserved in Surfl homologs of 12 species. The substitution G618 C (Asp202-->His), changing an Asp that is conserved only in mammals, appears to be a polymorphism. The mutation T751 C changes Ile246 to Thr, a position at which a hydrophobic amino acid is conserved in all eukaryotic and some bacterial species. Replacing Ile246 by Thr disrupts a predicted beta sheet structure present in all higher eukaryotes. COX activity could be restored in fibroblasts of the three patients by complementation with a retroviral vector containing normal SURF1 cDNA. These mutations identify domains essential to Surf1 protein structure and/or function.
authors.affiliation: Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Centre National de la Recherche Scientifique, Université Claude Bernard de Lyon I, Villeurbanne, France.
authors.forename: A
authors.initials: A
authors.lastname: Poyau
authors.forename: K
authors.initials: K
authors.lastname: Buchet
authors.forename: M F
authors.initials: MF
authors.lastname: Bouzidi
authors.forename: M T
authors.initials: MT
authors.lastname: Zabot
authors.forename: B
authors.initials: B
authors.lastname: Echenne
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.forename: E A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: C
authors.initials: C
authors.lastname: Godinot
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D018076:DNA, Complementary; D003576:Electron Transport Complex IV / Q000235:genetics*; D005816:Genetic Complementation Test; D006367:HeLa Cells; D006801:Humans; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C092928:Surf-1 protein; D003576:Electron Transport Complex IV