Leigh disease associated with a novel mitochondrial DNA ND5 mutation

Abstract

Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation.

Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease

“…The proportion of mutant DNA was quantified using a Storm PhosphorImager with ImageQuant software (Molecular Dynamics, Sunnyvale, CA). Other mtDNA mutations tested for by restriction frag- ment length polymorphism analysis were T12706C, 6 A13514G, 11 and G14459A. 5 For BN-PAGE analysis, mitochondria were isolated from patient cell lines according to Argan and colleagues 12 and stored in aliquots at Ϫ80°C until use.…”

“…Mitochondrial DNA genes include both complex I structural subunit (ND) genes and transfer RNA genes, particularly tRNA leucine UUR . 3 However, to date, only two mutations in mtDNA complex I subunits, G14459A in the ND6 gene, 5 and T12706C in the ND5 gene, 6 have been associated with complex I deficiency and LD. Another ND5 mutation, A13045C, has been described recently in association with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)/Leber's hereditary optic neuropathy (LHON)/LD overlap syndrome.…”

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

“…Therefore, ND5 might also play an important role in human mitochondria. Some recent reports have suggested the validity of this theory (Kirby et al 2000;Taylor et al 2002;Liolitsa et al 2003;Crimi et al 2003).…”

Leigh syndrome: One disorder, more than 75 monogenic causes

“…As a severe manifestation of mitochondrial disease, LS is typically associated with high mutant loads of 90%, although MTND5 mutations associated with complex I deficiency are notable for their propensity to cause LS even when the mutant load is <50% in tissues including brain, where patients have been observed to survive into adulthood. [52][53][54] Mutations in complex I subunits MTND3 and MTND5, and in the complex V subunit MTATP6, are the most frequent mtDNA causes of LS. MTATP6 mutations represent the only established genetic basis of complex V-mediated LS, and mutations in this gene are estimated to underlie 10% of all LS cases.…”