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- Title
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
- Authors
Strauss, Karsten M; Martins, L Miguel; Plun-Favreau, Helene; Marx, Frank P; Kautzmann, Sabine; Berg, Daniela; Gasser, Thomas; Wszolek, Zbginiew; Müller, Thomas; Bornemann, Antje; Wolburg, Hartwig; Downward, Julian; Riess, Olaf; Schulz, Jörg B; Krüger, Rejko
- Abstract
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.
- Publication
Human molecular genetics, 2005, Vol 14, Issue 15, p2099
- ISSN
0964-6906
- Publication type
Journal Article
- DOI
10.1093/hmg/ddi215