Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism

J Med Genet. 2008 Sep;45(9):596-602. doi: 10.1136/jmg.2008.058628. Epub 2008 Jun 4.


Aims and background: Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism.

Results: Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity.

Conclusion: To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cells, Cultured
  • DNA Mutational Analysis
  • DNA, Mitochondrial / analysis
  • DNA, Mitochondrial / chemistry*
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Female
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Genotype
  • Humans
  • Mutation, Missense*
  • Oxidative Phosphorylation
  • Parkinsonian Disorders / enzymology
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism
  • Phenotype
  • Protein Kinases / genetics*
  • Superoxides / metabolism


  • DNA, Mitochondrial
  • Superoxides
  • Protein Kinases
  • PTEN-induced putative kinase
  • Electron Transport Complex I