title: Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome.
abstract: BACKGROUND
  Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene.
  
  
  RESULTS
  A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers.
  
  
  CONCLUSIONS
  A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.
authors: Department of Genetics and Cell Biology, Unit Clinical Genomics, Maastricht University, Maastricht, The Netherlands.
authors: M
authors: M
authors: Gerards
authors: W
authors: W
authors: Sluiter
authors: B J C
authors: BJ
authors: van den Bosch
authors: L E A
authors: LE
authors: de Wit
authors: C M H
authors: CM
authors: Calis
authors: M
authors: M
authors: Frentzen
authors: H
authors: H
authors: Akbari
authors: K
authors: K
authors: Schoonderwoerd
authors: H R
authors: HR
authors: Scholte
authors: R J
authors: RJ
authors: Jongbloed
authors: A T M
authors: AT
authors: Hendrickx
authors: I F M
authors: IF
authors: de Coo
authors: H J M
authors: HJ
authors: Smeets
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D005190:Family; D005260:Female; D006720:Homozygote; D006801:Humans; D007888:Leigh Disease / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008279:Magnetic Resonance Imaging; D008297:Male; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009018:Morocco; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D008780:Methyltransferases; C532992:NDUFAF5 protein, human; D042967:Electron Transport Complex I