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Article (Scientific journals)
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
Strauss, Karsten M.; MARTINS, Luisa; Plun-Favreau, Helene et al.
2005In Human molecular genetics, 14 (15), p. 2099-111
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Keywords :
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
Abstract :
[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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
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 ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
More authors (5 more) Less
Language :
English
Title :
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.
Publication date :
2005
Journal title :
Human molecular genetics
ISSN :
0964-6906
Volume :
14
Issue :
15
Pages :
2099-111
Peer reviewed :
Peer reviewed
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