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.
- CSGE, conformation-sensitive gel electrophoresis
- LHON, Leber’s hereditary optic neuropathy
- mtDNA, mitochondrial DNA
- OXPHOS, oxidative phosphorylation
- RFLP, restriction fragment length polymorphism
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Published Online First 1 September 2006
Funding: This study was supported by grants from the Medical Research Council, Academy of Finland (project numbers 107490, 108953, 79843, 107174); the Sigrid Juselius Foundation; the Alma and KA Snellman Foundation, Oulu, Finland; the Päivikki and Sakari Sohlberg Foundation; the Foundation for Pediatric Research; the Arvo and Lea Ylppö Foundation; the Neurology Foundation; the Dutch Organisation for Scientific Research; and the Prinses Beatrix Fonds. CU is the recipient of a research contract from the Instituto de Salud Carlos III (ISCIII CP04/00011).
Competing interests: None.
Data access: GenBank database (http://www.ncbi.nlm.nih.gov), accession numbers DQ489500–DQ489527.