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Published online on December 4, 2006, 10.1073/pnas.0510836103
PNAS | December 12, 2006 | vol. 103 | no. 50 | 19164-19169


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

Chun-Hyung Kim*, Maureen K. Hahn{dagger}, Yoosook Joung{ddagger}, Susan L. Anderson§, Angela H. Steele{dagger}, Michelle S. Mazei-Robinson{dagger}, Ian Gizer, Martin H. Teicher§, Bruce M. Cohen||, David Robertson**, Irwin D. Waldman, Randy D. Blakely{dagger}, and Kwang-Soo Kim*,{dagger}{dagger}

*Molecular Neurobiology, §Developmental Psychopharmacology, and ||Molecular Pharmacology Laboratories, McLean Hospital, Harvard Medical School, Belmont, MA 02478; {dagger}Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37232; {ddagger}Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-170, Korea; Department of Psychology, Emory University, Atlanta, GA 30322; and **Autonomic Dysfunction Center, Departments of Medicine, Pharmacology, and Neurology, Vanderbilt University, Nashville, TN 37232

Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved October 16, 2006 (received for review December 19, 2005)

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.

Snail family | E2-box | Slug | Scratch

Author contributions: C.-H.K., Y.J., B.M.C., R.D.B., and K.-S.K. designed research; C.-H.K., M.K.H., and A.H.S. performed research; C.-H.K., S.L.A., I.G., M.H.T., D.R., I.D.W., and R.D.B. contributed new reagents/analytic tools; C.-H.K., S.L.A., M.S.M.-R., I.D.W., R.D.B., and K.-S.K. analyzed data; and C.-H.K., I.D.W., and K.-S.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0510836103/DC1.

{dagger}{dagger}To whom correspondence should be addressed. E-mail: kskim{at}mclean.harvard.edu

© 2006 by The National Academy of Sciences of the USA


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