Reference : Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
Scientific journals : Article
Life sciences : Genetics & genetic processes
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
Strauss, Karsten M. [> >]
Martins, Luisa []
Plun-Favreau, Helene [> >]
Marx, Frank P. [> >]
Kautzmann, Sabine [> >]
Berg, Daniela [> >]
Gasser, Thomas [> >]
Wszolek, Zbginiew [> >]
Muller, Thomas [> >]
Bornemann, Antje [> >]
Wolburg, Hartwig [> >]
Downward, Julian [> >]
Riess, Olaf [> >]
Schulz, Jorg B. [> >]
Krüger, Rejko mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Human molecular genetics
Yes (verified by ORBilu)
[en] Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Brain/metabolism ; Cell Death ; Cells, Cultured ; DNA Mutational Analysis ; Female ; Gene Expression Regulation ; Humans ; Male ; Membrane Potentials ; Mice ; Middle Aged ; Mitochondria/metabolism/ultrastructure ; Mitochondrial Proteins ; Models, Molecular ; Molecular Sequence Data ; Parkinson Disease/genetics/metabolism/pathology ; Point Mutation ; Sequence Homology, Amino Acid ; Serine Endopeptidases/genetics/metabolism ; Transfection
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)

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