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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 attention-deficit hyperactivity disorder and other neuropsychiatric diseases.

SUBMITTER: Kim CH

PROVIDER: S-EPMC1748193 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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

Kim Chun-Hyung CH Hahn Maureen K MK Joung Yoosook Y Anderson Susan L SL Steele Angela H AH Mazei-Robinson Michelle S MS Gizer Ian I Teicher Martin H MH Cohen Bruce M BM Robertson David D Waldman Irwin D ID Blakely Randy D RD Kim Kwang-Soo KS

Proceedings of the National Academy of Sciences of the United States of America 20061204 50

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 func ...[more]

PMID: 17146058

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Project description:BACKGROUND:Attention Deficit Hyperactivity Disorder (ADHD) can lead to drastic problems for the patient and its worldwide prevalence is 5%-12%. It also has many comorbidities with other disorders, and the genetic contribution seems the most significant cause. OBJECTIVES:The current study was conducted to investigate the association between norepinephrine transporter-3081 (A/T) polymorphisms and ADHD in Iranian population. PATIENTS AND METHODS:Participants were chosen from children and adolescents diagnosed with ADHD referred to Imam Hoseyn Hospital. A child and adolescent psychiatrist confirmed the diagnosis using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL) semi-structural interview. The control group was from pupils of schools in Tehran (capital city of Iran) who had no history or presence of psychiatric and medical complications. Also, a child and adolescent psychiatrist confirmed their health using the K-SADS-PL semi-structural interview. Genetic examinations were DNA distraction, Polymerase Chain Reaction (PCR), and Restricted Fragment Length Polymorphism (RFLP), which were conducted according to standard protocols. The statistical analysis was performed using chi-square and Fisher's exact test in SPSS version 21. RESULTS:The percentages of ADHD subtypes for combined, inattentive, and hyperactive/impulsive were 72.2%, 17.2%, and 11.9%, respectively. There was no significant association between norepinephrine transporter polymorphism and ADHD (P = 0.81). Moreover, no significant relationship was found between gender [male (P = 0.92) and female (P = 0.63)] and polymorphism. No significant association was found between subtypes of ADHD [combined (P = 0.46), inattentive (P = 0.41), hyperactive/impulsive (P = 0.32)] and polymorphism SCL6A2. This lack of association can also be seen in gender in every subtype. CONCLUSIONS:The results of the study show no significant association between norepinephrine transporter polymorphism SCL6A2 and ADHD.

Dataset Information

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

Publications

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

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