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Author Notes:

Kwang-Soo Kim: kskim@mclean.harvard.edu.

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.

We thank R. Steven Couch and Richard C. Shelton for assistance with collection of Pediatric ADHD subjects.

We also wish to recognize the contribution of David C. Rowe, who played an integral role in beginning the candidate gene study of ADHD at Emory University.

The authors declare no conflict of interest.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Snail family
  • E2-box
  • slug
  • scratch
  • BETA-HYDROXYLASE GENE
  • NO EVIDENCE
  • NORADRENALINE TRANSPORTER
  • TRANSCRIPTION FACTORS
  • K-SADS
  • CHILDREN
  • LINKAGE
  • ADHD
  • SCHIZOPHRENIA
  • TACHYCARDIA

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

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 103, Number 50

Publisher:

, Pages 19164-19169

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2006 by The National Academy of Sciences of the USA.

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