Journal Article

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

Karsten M. Strauss, L. Miguel Martins, Helene Plun-Favreau, Frank P. Marx, Sabine Kautzmann, Daniela Berg, Thomas Gasser, Zbginiew Wszolek, Thomas Müller, Antje Bornemann, Hartwig Wolburg, Julian Downward, Olaf Riess, Jörg B. Schulz and Rejko Krüger

in Human Molecular Genetics

Volume 14, issue 15, pages 2099-2111
Published in print August 2005 | ISSN: 0964-6906
Published online June 2005 | e-ISSN: 1460-2083 | DOI:
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease

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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.

Journal Article.  7570 words.  Illustrated.

Subjects: Genetics and Genomics

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