Functional association of the parkin gene promoter with idiopathic Parkinson's disease.
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.
West
Andrew B
AB
Laboratories of Neurogenetics, Department of Neuroscience, Mayo Clinic Jacksonville, FL 32224, USA.
Maraganore
Demetrius
D
Crook
Julia
J
Lesnick
Tim
T
Lockhart
Paul J
PJ
Wilkes
Kristen M
KM
Kapatos
Gregory
G
Hardy
John A
JA
Farrer
Matt J
MJ
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
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D004247:DNA; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases