31 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 2005 Human molecular genetics 14 15 2099-111 2005 Aug 1 Hum. Mol. Genet. http://www.ncbi.nlm.nih.gov/pubmed/15961413?dopt=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.