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

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 attentiondeficit hyperactivity disorder and other neuropsychiatric diseases.Snail family ͉ E2-box ͉ Slug ͉ Scratch

Further evidence of association between two NET single-nucleotide polymorphisms with ADHD

“…39 Recently, a novel SNP (À3081[A/T]) in the nearby promoter was identified and reported to be modestly associated with ADHD in a set of 94 ADHD cases and 60 controls (P = 0.029). 23 Although this SNP is currently not available in the public database, the location of À3081[A/T] is 3081 bp upstream of the transcription start site and there were no indications that recombination had occurred between rs3785143 and SNPs around this upstream region (D 0 = 1) (Figure 1). So it is also possible that this association may have been due to high LD with rs3785143.…”

“…[18][19][20][21][22][23][24][25] Earlier studies investigated only a few genetic markers in NET and found no evidence of association. [18][19][20] Xu et al…”

“…Recently, a novel promoter SNP showed some evidence of association in a set of 94 ADHD cases and 60 controls (P = 0.029). 23 Additionally, a methylphenidate response study of ADHD found that a synonymous SNP rs5569 (1287G/A) in exon 9 was associated with response to the drug (P = 0.012). 24 However, none of these results were replicated, and it is currently unclear whether there exists an association between ADHD and NET.…”

Animal Models of Attention-Deficit/Hyperactivity Disorder

“…9) Other gene variants also have been suggested to be associated with AD/HD such as genes that encode monoamine oxidase A, dopamine b-hydroxylase, norepinephrine transporter (NET), and a2-adrenoceptor. [10][11][12] It is also thought that the gene-environment interactions exist in the etiology of AD/HD. The most consistent and robustly associated results are prenatal exposure to nicotine from smoking in utero.…”

Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter

“…Since NE is a fundamental neurochemical messenger, its accurate regulation is of major importance. Thus, the NET, responsible for NE equilibrium in the synaptic cleft, is representing the reuptake site and considered to be involved in a variety of neurological/psychiatric disorders [1,2], but also plays a pivotal role in cardiovascular [1][2][3] and metabolic diseases [3][4][5]. Reduced NET levels go along with neurological disorders like major depression [6,7], Parkinson's disease (PD), Alzheimer's disease (AD) [8][9][10][11][12][13][14][15][16][17][18], and cardiovascular diseases such as hypertension, cardiomyopathy, and heart failure [5,13].…”