Abstract

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.