Human Molecular Genetics Advance Access published online on June 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi215
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1 Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
* To whom correspondence should be addressed. 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 PD patients. In four patients we identified a novel heterozygous G399S mutation, that was absent in healthy controls. Moreover we identified a novel A141S polymorphism that was associated with PD (p<.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 (WT). Based on functional genomics our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.
Received February 26, 2005
Revised June 7, 2005
Accepted June 7, 2005
Article
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease
2 MRC Toxicology Unit, Leicester, UK
3 Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK
4 Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Department of Medical Genetics, University of Tübingen, Tübingen, Germany
5 Department of Neurology, Mayo Clinic Jacksonville, USA
6 Department of Neurology, Ruhr-University Bochum, Bochum, Germany
7 Institute of Brain Research, University of Tübingen, Tübingen, Germany
8 Institute of Pathology, University of Tübingen, Tübingen, Germany
9 Department of Medical Genetics, University of Tübingen, Tübingen, Germany
Jörg B. Schulz1, E-mail: jschulz4{at}gwdg.de
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