Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
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.
Strauss
Karsten M
KM
Center of Neurology and Hertie-Institute for Clinical Brain Research, Leicester, UK.
Martins
L Miguel
LM
Plun-Favreau
Helene
H
Marx
Frank P
FP
Kautzmann
Sabine
S
Berg
Daniela
D
Gasser
Thomas
T
Wszolek
Zbginiew
Z
Müller
Thomas
T
Bornemann
Antje
A
Wolburg
Hartwig
H
Downward
Julian
J
Riess
Olaf
O
Schulz
Jörg B
JB
Krüger
Rejko
R
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
D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse