title: Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease.
abstract: Respiratory chain complex I deficiency is a common cause of Leigh's disease (LD) and can be caused by mutations in genes encoded by either nuclear or mitochondrial DNA (mtDNA). Most pathogenic mtDNA mutations act recessively and only cause disease when present at high mutant loads (typically >90%) in tissues such as muscle and brain. Two mitochondrial DNA mutations in complex I subunit genes, G14459A in ND6, and T12706C in ND5, have been associated with complex I deficiency and LD. We report another ND5 mutation, G13513A, in three unrelated patients with complex I deficiency and LD. The G13513A mutation was present at mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. Blue Native polyacrylamide gel electrophoresis showed that fibroblasts with 45% G13513A mutant load had approximately 50% of the normal amount of fully assembled complex I. Fibroblasts with greater than 97% of the ND6 G14459A mutation had only 20% fully assembled complex I, suggesting that both mutations disrupt complex I assembly or turnover. We conclude that the G13513A mutation causes a complex I defect when present at unusually low mutant load and may act dominantly.
authors.affiliation: Murdoch Children's Research Institute, University of Melbourne, Victoria, Australia.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kirby
authors.forename: Avihu
authors.initials: A
authors.lastname: Boneh
authors.forename: C W
authors.initials: CW
authors.lastname: Chow
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.forename: Dominic
authors.initials: D
authors.lastname: Thyagarajan
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
mesh_terms: D000328:Adult; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D007888:Leigh Disease / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology; D018482:Muscle, Skeletal / Q000276:immunology; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000378:metabolism; D017354:Point Mutation
chemical_list: D004272:DNA, Mitochondrial; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I