Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder.
Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder.
复制标题
DOI：
10.1016/j.neuropharm.2009.08.002
复制
发表时间：
2009-12
影响因子：
4.7
通讯作者：
Krueger, Jessica J.
中科院分区：
文献类型：
--
作者：
Hahn, Maureen K.;Steele, Angela;Couch, R. Steven;Stein, Mark A.;Krueger, Jessica J.
注意缺陷多动障碍（ADHD）是一种高度遗传性的行为抑制受损、运动活动增加和注意力不集中的疾病。去甲肾上腺素转运蛋白（NET, SLC6A2）是ADHD的重要候选基因，因为它调节儿茶酚胺细胞外和组织浓度，并有助于ADHD的执行功能中断，NET是最有效的ADHD治疗靶点。我们在两个ADHD样本集中鉴定了4个NET编码单核苷酸多态性（SNPs），其中两个SNPs产生蛋白质变体（T283M, V245I），其中一个T283M是一个新变体。通过T283M突变传播的母亲家庭成员的检查，没有提供额外的ADHD诊断。考虑到先前发现的NET突变导致家族性心动过速综合征，我们检查了自主神经功能，以揭示在被检查的ADHD受试者中，先证者站立引起的心率增加最高。我们测量了T283M、V245I和先前鉴定的NET变体T283R的[3H]NE和[3H]多巴胺转运。T283M和V245I显示底物运输减少，T283R也是如此，表明T283残基对突变敏感。识别NET中的多态性位点，特别是那些产生功能后果的位点，是阐明导致ADHD等疾病遗传成分的遗传变异的关键一步。
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, V245I), 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 [3H]NE and [3H]dopamine transport for T283M, V245I, and a previously identified NET variant, T283R. T283M and V245I 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.
登录
查看更多内容
影响因子：
10.6
作者：
Dlugos, Andrea;Freitag, Christine;de Wit, Harriet
通讯作者：
de Wit, Harriet
影响因子：
3.6
作者：
Hahn, MK;Mazei-Robison, MC;Blakely, RD
通讯作者：
Blakely, RD
影响因子：
11
作者：
Brookes, K.;Xu, X.;Johansson, L.
通讯作者：
Johansson, L.
影响因子：
10.6
作者：
Aston-Jones, G;Rajkowski, J;Cohen, J
通讯作者：
Cohen, J
影响因子：
2.5
作者：
Hahn, M. K.;Blackford, J. U.;Shelton, R.
通讯作者：
Shelton, R.