title: Functional association of the parkin gene promoter with idiopathic Parkinson's disease.
abstract: Loss-of-function mutations in the parkin gene were first identified in autosomal recessive juvenile parkinsonism (AR-JP). Subsequently, parkin mutations were found in many early-onset patients with Parkinson's disease (PD) (<45 years at onset). We hypothesized that parkin gene expression also may contribute to the age-associated risk of idiopathic PD (>50 years at onset). Two single-nucleotide polymorphisms within the parkin core promoter have been identified and assessed. We show one of the variants, -258 T/G, is located in a region of DNA that binds nuclear protein from human substantia nigra in vitro and functionally affects gene transcription. Furthermore, the -258 T/G polymorphism is genetically associated with idiopathic PD, as assessed in a large population-based series of cases and controls. Our results further implicate the parkin gene in the development of Parkinson's disease.
authors.affiliation: Laboratories of Neurogenetics, Department of Neuroscience, Mayo Clinic Jacksonville, FL 32224, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
authors.forename: Demetrius
authors.initials: D
authors.lastname: Maraganore
authors.forename: Julia
authors.initials: J
authors.lastname: Crook
authors.forename: Tim
authors.initials: T
authors.lastname: Lesnick
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Wilkes
authors.forename: Gregory
authors.initials: G
authors.lastname: Kapatos
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000368:Aged; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008025:Ligases / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013378:Substantia Nigra / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D004247:DNA; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases