title: Mutations in NR4A2 associated with familial Parkinson disease.
abstract: NR4A2, encoding a member of nuclear receptor superfamily, is essential for the differentiation of the nigral dopaminergic neurons. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.
authors.affiliation: Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. Weidongl@bcm.tmc.edu
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Le
authors.forename: Pingyi
authors.initials: P
authors.lastname: Xu
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Appel
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
authors.forename: Demetrios K
authors.initials: DK
authors.lastname: Vassilatis
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D014157:Transcription Factors