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

Human molecular genetics | Aug 1, 2005

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 RIS Download

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

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Associated grants

  • Agency: Medical Research Council, Id: MRC_MC_U132674518

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