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

By K. Strauss, L. Martins, H. Plun-Favreau, Frank P. Marx, Sabine Kautzmann, D. Berg, T. Gasser, Z. Wszolek, T. Müller, A. Bornemann and 6 more. Human Molecular Genetics, 2005

597 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/c036d3964ebf722d4725bfa95f5a5bdc0acbf0db

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In Cellular and Molecular Neuroscience

1. M. Beal
2. E. K. Kim
3. E. Choi

In Neurology

1. M. Beal
2. E. K. Kim
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4. Zena Werb
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Citations in the corpus

• Epidemiology and etiology of Parkinson’s disease: a review of the evidence (2011, background): “Omi/HtrA2 (PARK13) 2p12 Dominant None Strauss [182]”
• Mitochondria take center stage in aging and neurodegeneration (2005, background): “Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the MPT by ROS.(82) Interestingly, mutations in Omi that reduce its protease activity increase the risk of PD.”
• Mitochondria, oxidative stress and neurodegeneration. (2012, background): “Mutations in HTRA2 determine mitochondrial swelling and lower mitochondrial membrane potential [69].”
• Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases (2006, unknown): “The gene most recently associated with PD is HTRA2 (also known as OMI”
• Expanding insights of mitochondrial dysfunction in Parkinson's disease (2006, background): “Recently, variation and mutation of the HtrA serine peptidase 2 ( HTRA2 , also known as OMI ) gene has also been tentatively associated with P”
• Parkinson's disease: from monogenic forms to genetic susceptibility factors. (2009, background): “Omi/Htra2, a mitochondrial-targeted serine protease released into the cytosol during apoptosis, has been implicated in PD pathogenesis on the basis of biological and genetic evidence (91).”
• Pathological roles of MAPK signaling pathways in human diseases. (2010, background): “The G399S mutation of HtrA2 results in a decrease in protease activity and has been associated with sporadic PD [122].”
• Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy (2008, background): “, 2004), and mutations in high temperature requirement A2 (HTRA2, also known as OMI, encoding a mitochondrial serine protease) in sporadic PD patients (Strauss et al., 2005), provide a compelling molecular link to mitochondrial function.”
• Mitochondrial Dysfunction in Parkinson's Disease (2011, background): “Omi/Htra2 is a mitochondrially located stress protective serine protease which has been linked to neurodegeneration [107, 108] with loss of function mutations being seen in some PD patients [109].”