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Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.

Pubmed ID: 15961413


  • Strauss KM
  • Martins LM
  • Plun-Favreau H
  • Marx FP
  • Kautzmann S
  • Berg D
  • Gasser T
  • Wszolek Z
  • Müller T
  • Bornemann A
  • Wolburg H
  • Downward J
  • Riess O
  • Schulz JB
  • Krüger R


Human molecular genetics

Publication Data

August 1, 2005

Associated Grants

  • Agency: Medical Research Council, Id: MC_U132674518

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Brain
  • Cell Death
  • Cells, Cultured
  • DNA Mutational Analysis
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • Membrane Potentials
  • Mice
  • Middle Aged
  • Mitochondria
  • Mitochondrial Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Parkinson Disease
  • Point Mutation
  • Sequence Homology, Amino Acid
  • Serine Endopeptidases
  • Transfection