Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome

J Med Genet. 2010 Aug;47(8):507-12. doi: 10.1136/jmg.2009.067553. Epub 2009 Jun 18.


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.

Methods and 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Base Sequence
  • Child, Preschool
  • DNA Mutational Analysis
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism*
  • Family
  • Female
  • Homozygote
  • Humans
  • Leigh Disease / diagnostic imaging
  • Leigh Disease / enzymology*
  • Leigh Disease / genetics*
  • Leigh Disease / metabolism
  • Leukocytes, Mononuclear / enzymology
  • Magnetic Resonance Imaging
  • Male
  • Methyltransferases / chemistry
  • Methyltransferases / genetics*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Molecular Sequence Data
  • Morocco
  • Mutation / genetics*
  • Pedigree
  • Tomography, X-Ray Computed
  • Young Adult


  • Mitochondrial Proteins
  • Methyltransferases
  • NDUFAF5 protein, human
  • Electron Transport Complex I