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, Rejko Krüger

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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.

Original languageEnglish (US)
Pages (from-to)2099-2111
Number of pages13
JournalHuman molecular genetics
Volume14
Issue number15
DOIs
StatePublished - Aug 1 2005

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Müller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., & Krüger, R. (2005). Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human molecular genetics, 14(15), 2099-2111. https://doi.org/10.1093/hmg/ddi215