Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease
2005 | journal article. A publication with affiliation to the University of Göttingen.
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Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease
Strauss, K. M.; Martins, L. M.; Plun-Favreau, H.; Marx, F. P.; Kautzmann, S.; Berg, D. & Gasser, T. et al. (2005)
Human Molecular Genetics, 14(15) pp. 2099-2111. DOI: https://doi.org/10.1093/hmg/ddi215
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- Authors
- Strauss, K. M.; Martins, L. Miguel; Plun-Favreau, H.; Marx, F. P.; Kautzmann, S.; Berg, Daniela; Gasser, Thomas; Wszolek, Zbigniew; Mueller, T.; Bornemann, Antje; Wolburg, Hartwig; Downward, J.; Riess, Olaf; Schulz, Joerg 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.
- Issue Date
- 2005
- Journal
- Human Molecular Genetics
- ISSN
- 0964-6906
- Sponsor
- Medical Research Council [MC_U132674518]