title: Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease.
abstract: In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5' and 3' regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bogaerts
authors.forename: Karen
authors.initials: K
authors.lastname: Nuytemans
authors.forename: Joke
authors.initials: J
authors.lastname: Reumers
authors.forename: Philippe
authors.initials: P
authors.lastname: Pals
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Barbara
authors.initials: B
authors.lastname: Pickut
authors.forename: Ellen
authors.initials: E
authors.lastname: Corsmit
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001530:Belgium; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D008928:Mitochondria; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2