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.

Leigh syndrome caused by mitochondrial DNA G13513A mutation: frequency and clinical features in Japan

“…We think it unnecessary to use the term Leighlike because the brainstem lesion is essential for LS. A recent report also used Leigh disease for three patients with this mutation, two of whom had no radiological involvement of basal ganglia (Kirby et al 2003). Three of our six patients with the G13513A mutation showed involvement of both brainstem and basal ganglia, and the remaining three showed a selective brainstem involvement.…”

“…A severely damaged region may have more mutant mtDNA and hence profound enzyme deficiency. Very recently, Kirby et al (2003) reported that mutant loads of approximately 50% or less induced the defect in complex I amount and activity in skeletal muscle, liver, and fibroblasts. We could not detect apparent enzyme deficiency in the skeletal muscles with the mutant proportion from 42 to 64%.…”

The mitochondrial 13513G>A mutation is most frequent in Leigh syndrome combined with reduced complex I activity, optic atrophy and/or Wolff–Parkinson–White

“…Three of them (6.0%), all with LS, carried the m.13513G4A mutation. Kirby et al 7 detected the mutation in three out of 86 patients (3.5%) with a complex I deficiency, including 30 with LS. All their positive cases also clinically had LS.…”

Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients

“…The m.13513AϾG transition in the ND5 gene changes an amino acid strongly conserved over 11 species (Table 1) and has been related to MELAS and Leigh syndrome in several reports. [23][24][25][26][27][28] The pathogenicity score for this mutation is 39. 22 The functional importance of this amino acid is further supported by the finding of a pathogenic mutation m.13514AϾG, affecting the same codon, that results in a different amino acid replacement (D393G vs. D393N) in two MELAS patients.…”