A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder.
The norepinephrine transporter critically regulates both neurotransmission and homeostasis of norepinephrine in the nervous system. In this study, we report a previously uncharacterized and common A/T polymorphism at -3081 upstream of the transcription initiation site of the human norepinephrine transporter gene [solute carrier family 6, member 2 (SLC6A2)]. Using both homologous and heterologous promoter-reporter constructs, we found that the -3081(T) allele significantly decreases promoter function compared with the A allele. Interestingly, this T allele creates a new palindromic E2-box motif that interacts with Slug and Scratch, neural-expressed transcriptional repressors binding to the E2-box motif. We also found that both Slug and Scratch repress the SLC6A2 promoter activity only when it contains the T allele. Finally, we observed a significant association between the -3081(A/T) polymorphism and attention-deficit hyperactivity disorder (ADHD), suggesting that anomalous transcription factor-based repression of SLC6A2 may increase risk for the development of attention-deficit hyperactivity disorder and other neuropsychiatric diseases.
Kim
Chun-Hyung
CH
Molecular Neurobiology, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Hahn
Maureen K
MK
Joung
Yoosook
Y
Anderson
Susan L
SL
Steele
Angela H
AH
Mazei-Robinson
Michelle S
MS
Gizer
Ian
I
Teicher
Martin H
MH
Cohen
Bruce M
BM
Robertson
David
D
Waldman
Irwin D
ID
Blakely
Randy D
RD
Kim
Kwang-Soo
KS
D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D016335:Zinc Fingers
D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D014157:Transcription Factors; D004247:DNA