Background: Leigh syndrome is an early-onset progressive neurodegenerative disorder with developmental and motor skills regression. Characteristic MRI abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation (OXPHOS) due to mutations in one of the mtDNA or nuclear OXPHOS genes.
Methods and results: Here we report on a mutation in a new complex I assembly gene C20orf7 in a consanguineous Moroccan family with Leigh syndrome. The family consists of 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5Mb 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 10% of the normal population and enzyme activity was only reduced to 50%, this could not explain the clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7. 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: We conclude that a new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.