A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder

• Type of Material: Article
• Authors: Chun-Hyung Kim, Harvard Medical School; Maureen K. Hahn, Vanderbilt University Medical Center; Yoosook Joung, Sungkyunkwan University School of Medicine; Susan L. Anderson, Harvard Medical School; Angela H. Steele, Vanderbilt University Medical Center; Michelle S. Mazei-Robinson, Vanderbilt University Medical Center; Ian Gizer, Emory University; Martin H. Teicher, Harvard Medical School; Bruce M. Cohen, Harvard Medical School; David Robertson, Vanderbilt University; Irwin Waldman, Emory University; Randy D. Blakely, Vanderbilt University Medical Center; Kwang-Soo Kim, Harvard Medical School
• Language: English
• Date: 2006-12-12
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2006 by The National Academy of Sciences of the USA.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.0510836103
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 103
• Issue: 50
• Start Page: 19164
• End Page: 19169
• Grant/Funding Information: This work was supported by National Institutes of Health Grants MH48866 and DC006501; and a NARSAD Independent award (to K.-S.K.); by National Institutes of Health Grant HL56693 (to R.D.B.); and by National Institute of Mental Health Grants K01-MH01818 (to I.D.W.) and F31-MH072083 (to I.G.).
• Keywords: Snail family; Science & Technology - Other Topics; LINKAGE; K-SADS; NORADRENALINE TRANSPORTER; scratch; TACHYCARDIA; Multidisciplinary Sciences; SCHIZOPHRENIA; slug; NO EVIDENCE; E2-box; TRANSCRIPTION FACTORS; CHILDREN; BETA-HYDROXYLASE GENE; Science & Technology; ADHD
• Research Categories: Health Sciences, Mental Health; Psychology, Clinical; Biology, Genetics

Abstract

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.