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Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency
  1. R Hinttala1,
  2. R Smeets2,
  3. J S Moilanen4,
  4. C Ugalde3,
  5. J Uusimaa5,
  6. J A M Smeitink,
  7. K Majamaa5
  1. 1Department of Neurology, University of Oulu, Oulu, Finland
  2. 2Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, University Medical Centre Nijmegen, Nijmegen, The Netherlands
  3. 3Institute of Medical Technology, University of Tampere, Finland
  4. 4Department of Pediatrics, University of Oulu, Oulu, Finland
  5. 5Department of Neurology, University of Turku, Turku, Finland
  1. Correspondence to:
 K Majamaa
 Department of Neurology, University of Turku, FIN-20014 Turku, Finland; kari.majamaa{at}


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 (, accession numbers DQ489500–DQ489527.