Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome
Open Access
- 18 June 2009
- journal article
- research article
- Published by BMJ in Journal of Medical Genetics
- Vol. 47 (8), 507-512
- https://doi.org/10.1136/jmg.2009.067553
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. 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.Keywords
This publication has 42 references indexed in Scilit:
- Progressive Encephalopathy and Complex I Deficiency Associated with Mutations in MTND1Neuropediatrics, 2008
- Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiencyJournal of Medical Genetics, 2006
- Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndromeJournal of Medical Genetics, 2004
- Genetic Features of Mitochondrial Respiratory Chain DisordersJournal of the American Society of Nephrology, 2003
- De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiencyAnnals of Neurology, 2003
- Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 geneAnnals of Neurology, 2003
- Leigh disease associated with a novel mitochondrial DNA ND5 mutationEuropean Journal of Human Genetics, 2002
- Large-Scale Deletion and Point Mutations of the Nuclear NDUFV1 and NDUFS1 Genes in Mitochondrial Complex I DeficiencyAmerican Journal of Human Genetics, 2001
- Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsyNature Genetics, 1999
- Getting to the Nucleus of Mitochondrial Disorders: Identification of Respiratory Chain–Enzyme Genes Causing Leigh SyndromeAmerican Journal of Human Genetics, 1998