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

• 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
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 103, Number 50
• Publisher: National Academy of Sciences | 2006-12-12, Pages 19164-19169
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.0510836103
• Subjects: Biology, Genetics; Health Sciences, Mental Health; Psychology, Clinical
• 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

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.