title: Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
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.
authors.affiliation: Center of Neurology and Hertie-Institute for Clinical Brain Research, Leicester, UK.
authors.forename: Karsten M
authors.initials: KM
authors.lastname: Strauss
authors.forename: L Miguel
authors.initials: LM
authors.lastname: Martins
authors.forename: Helene
authors.initials: H
authors.lastname: Plun-Favreau
authors.forename: Frank P
authors.initials: FP
authors.lastname: Marx
authors.forename: Sabine
authors.initials: S
authors.lastname: Kautzmann
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Zbginiew
authors.initials: Z
authors.lastname: Wszolek
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse