Behavioural genetics of the serotonin transporter.
Behavioural genetics of the serotonin transporter.
复制标题
DOI：
10.1007/7854_2011_186
复制
发表时间：
2012
影响因子：
--
通讯作者：
K. Haddley;V. Bubb;G. Breen;U. M. Parades-Esquivel;J. Quinn
中科院分区：
文献类型：
--
作者：
K. Haddley;V. Bubb;G. Breen;U. M. Parades-Esquivel;J. Quinn
5-羟色胺转运蛋白是5-羟色胺生物利用度的关键调节剂，因此转运蛋白表达或作用的任何调节预期都会对行为产生影响。因此，转运蛋白已成为行为和情绪障碍药物干预的目标。对与神经系统疾病相关的转运蛋白多态性变体的研究已经很广泛，但已经集中在两个领域，这两个领域都被称为可变数目串联重复序列（VNTR）多态性。这两种VNTR都在非编码DNA中，因此提出通过它们调节转运蛋白的转录或转录后调节的能力在机制上参与疾病。研究最广泛的是启动子，是在转录起始位点上游1.2 kb的基因5′启动子区发现的双等位基因插入/缺失。这种VNTR，称为5-HTTLPR，最初被鉴定为含有14个（短/缺失）或16个（长/插入）拷贝的22 bp重复的两种变体。在转运蛋白的非编码区中发现的第二种广泛研究的VNTR位于内含子2内，并且包含分别称为STin2.9、STin2.10和STin2.12的9、10或12个拷贝的16-17 bp重复。这些VNTR多态性与一系列行为和精神障碍相关，包括抑郁症，强迫症，焦虑症和精神分裂症，然而，在不同的队列中缺乏可重复性往往导致对多态性与这种广泛的神经系统疾病的实际关联的争论。在这里，我们审查这两个多态性VNTR的深入和药物反应，他们的能力，调节差异转运蛋白的表达，他们的核心参与基因-环境相互作用及其与特定疾病的遗传关联。
The serotonin transporter is a key regulator of the bioavailability of serotonin and therefore any modulation in the expression or action of the transporter would be expected to have consequences on behaviour. The transporter has therefore become a target for pharmaceutical intervention in behavioural and mood disorders. The search for polymorphic variants in the transporter that would associate with neurological disorders has been extensive but has become focused on two domains which are both termed variable number tandem repeat (VNTR) polymorphisms. Both of these VNTRs are in non-coding DNA and therefore proposed to be mechanistically involved in a disorder through their ability to modulate transcriptional or post-transcriptional regulation of the transporter. The most extensively studied is in the promoter and is a bi-allelic insertion/deletion found in the 5′ promoter region of the gene 1.2 kb upstream of the transcriptional start site. This VNTR, termed, 5-HTTLPR was initially identified as two variants containing either, 14 (short/deletion) or 16 (long/insertion) copies of a 22 bp repeat. A second widely studied VNTR found in the non-coding region of the transporter is located within intron 2 and comprises 9, 10 or 12 copies of a 16–17 bp repeat termed, STin2.9, STin2.10 and STin2.12, respectively. These VNTR polymorphisms have been associated with a range of behavioural and psychiatric disorders including depression, OCD, anxiety and schizophrenia, however often the lack of reproducibility in different cohorts has led to debate on the actual association of the polymorphisms with this extensive range of neurological conditions. Here we review these two polymorphic VNTRs in depth and relate that to pharmaceutical response, their ability to regulate differential transporter expression, their core involvement in gene-environment interaction and their genetic association with specific disorders.