Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder

NEUROPHARMACOLOGY

卷:57

Article

Hahn, Maureen K.^1,2,3  Couch, R. Steven^4,5  Stein, Mark A.⁶  Krueger, Jessica J.³ 

[1] Vanderbilt Univ, Sch Med, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Ctr Mol Neurosci, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Dept Med, Div Med Genet, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Med Ctr, Div Dev Med & Cognit, Nashville, TN 37232 USA

[6] Univ Illinois, Dept Psychiat, Chicago, IL 60608 USA

关键词: Norepinephrine;    Transporter;    Gene;    SNP;    Polymorphism;    Attention-deficit hyperactivity disorder;   

DOI  :  10.1016/j.neuropharm.2009.08.002

来源: Elsevier

【 摘 要 】

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable disorder of impaired behavioral inhibition, increased motor activity, and inattention. The norepinephrine transporter (NET, SLC6A2) represents an important candidate gene for contribution to ADHD because it regulates catecholamine extracellular and tissue concentrations and contributes to executive functions disrupted in ADHD, and NET is a target for most effective ADHD therapeutics. We identified four NET coding single nucleotide polymorphisms (SNPs) in two ADHD sample sets; two SNPs produce protein variants (T283M, V2451), one of which, T283M, is a novel variant Examination of the maternal family members through whom the T283M mutation was transmitted, provided no additional ADHD diagnoses. Given the previous identification of a NET mutation that contributes to a familial tachycardia syndrome, we examined autonomic function to reveal in the proband the highest standing-induced increase in heart rate among the ADHD subjects examined. We measured [(3)H]NE and [(3)H]dopamine transport for T283M, V2451, and a previously identified NET variant, T283R. T283M and V2451 demonstrated decreased substrate transport, as did T283R, suggesting that the T283 residue is sensitive to mutation. Identification of polymorphic sites within NET, specifically those that produce functional consequences, is one critical step in elucidating the genetic variation contributing to the heritable component of diseases such as ADHD. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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