Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency.

BACKGROUND: Enzyme deficiencies of the oxidative phosphorylation (OXPHOS) system may be caused by mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA.
OBJECTIVE: To analyse the sequences of the mtDNA coding region in 25 patients with OXPHOS system deficiency to identify the underlying genetic defect.
RESULTS: Three novel non-synonymous substitutions in protein-coding genes, 4681T-->C in MT-ND2, 9891T-->C in MT-CO3 and 14122A-->G in MT-ND5, and one novel substitution in the 12S rRNA gene, 686A-->G, were found. The definitely pathogenic mutation 3460G-->A was identified in an 18-year-old woman who had severe isolated complex I deficiency and progressive myopathy.
CONCLUSIONS: Bioinformatic analyses suggest a pathogenic role for the novel 4681T-->C substitution found in a boy with Leigh's disease. These results show that the clinical phenotype caused by the primary Leber's hereditary optic neuropathy mutation 3460G-->A is more variable than has been thought. In the remaining 23 patients, the role of mtDNA mutations as a cause of the OXPHOS system deficiency could be excluded. The deficiency in these children probably originates from mutations in the nuclear genes coding for respiratory enzyme subunits or assembly factors.