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Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome
  1. M Gerards1,2,
  2. W Sluiter3,
  3. B J C van den Bosch1,2,
  4. L E A de Wit3,
  5. C M H Calis1,
  6. M Frentzen4,
  7. H Akbari4,
  8. K Schoonderwoerd5,
  9. H R Scholte3,6,
  10. R J Jongbloed1,
  11. A T M Hendrickx1,
  12. I F M de Coo7,
  13. H J M Smeets1,2
  1. 1Department of Genetics and Cell Biology, Unit Clinical Genomics, Maastricht University, Maastricht, The Netherlands
  2. 2School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
  3. 3Department of Biochemistry, Mitochondrial Research Unit, Erasmus MC, Rotterdam, The Netherlands
  4. 4Unit of Botany, Institute for Biology I, RWTH Aachen University, Aachen, Germany
  5. 5Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
  6. 6Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands
  7. 7Department of Neurology, Erasmus MC, Rotterdam, The Netherlands
  1. Correspondence to Dr H J M Smeets, Department of Genetics and Cell Biology, PO Box 616, 6200 MD Maastricht, the Netherlands; Bert.Smeets{at}


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.

  • C20orf7
  • Leigh
  • complex I
  • genetics
  • clinical genetics

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  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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