title: Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder.
abstract: Attention deficit hyperactivity disorder (ADHD) is a highly heritable and common disorder thought to arise, in part, from alterations in dopamine function. NR4A2, or Nurr1, is an orphan nuclear receptor implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN). Dopaminergic cells of the VTA provide innervation to the prefrontal cortex, believed to be of major importance in the etiology of ADHD, suggesting that NR4A2 is a potential candidate gene for ADHD susceptibility. This study aimed to identify polymorphisms in NR4A2 and test their association to ADHD. Database analysis revealed a CA repeat polymorphism in the 3' UTR of NR4A2 that was confirmed by PCR. SSCP screening revealed a common DeltaC polymorphism, 254 bp 5' to the transcriptional start site. These polymorphisms were tested for an association with ADHD in both a case control study of individuals from the Milwaukee Longitudinal Study of ADHD (103 cases and 66 controls), and in 35 families composed of trios or affected sib pairs (ASP) with ADHD. Functional effects of the promoter polymorphism were tested in vitro. The non-deleted allele was significantly more active in undifferentiated SK-N-MC cells compared to differentiated SK-N-MC and HeLa cells while a trend for increased activity for the DeltaC allele was observed in undifferentiated SK-N-MC cells. Identification of these polymorphisms may aid future candidate gene studies in disorders with altered dopamine signaling, such as schizophrenia Parkinson's disease and ADHD.
authors.affiliation: Genetics Program, Sackler School of GBS, Tufts University, Boston, Massachusetts, USA.
authors.forename: Karen Müller
authors.initials: KM
authors.lastname: Smith
authors.forename: Lorri
authors.initials: L
authors.lastname: Bauer
authors.forename: Mariellen
authors.initials: M
authors.lastname: Fischer
authors.forename: Russell
authors.initials: R
authors.lastname: Barkley
authors.forename: Bradford A
authors.initials: BA
authors.lastname: Navia
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D015870:Gene Expression; D005838:Genotype; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases