The establishment of diagnostic and therapeutic method for mood and axiety disorders Pharmacogenetical analysis of serotonin transporter gene

5-羟色胺转运体(5-HTT)参与突触前5-羟色胺的再摄取，终止和调节5-羟色胺能神经传递。5-羟色胺是广泛使用的再摄取抑制抗抑郁药的作用部位。因此，5-HTT功能障碍与诸如情绪和焦虑症等精神疾病的病因学有关。人类5-HTT基因已被克隆并定位在染色体17q11.1-q12上。最近，在该基因的转录控制区(5-HTTLPR)中发现了一种多态性，它由不同长度的重复序列组成，该重复序列在该基因的上游调控区含有20~23bp的富含GC的重复元件。5-HTTLPR中的缺失/插入产生一个短(S)等位基因和一个长(L)等位基因(14-和16-重复等位基因)，从而改变启动子的活性。我们对5-HTTLPR进行了详细的分析，除了以前报道的序列外，还鉴定了10个新的序列，并证明了它们在日本人和高加索人中的分布差异。用含有PGL-3启动子载体的SHTTLPR-序列在包括小鼠中缝核来源的RN46A在内的几个细胞系中检测了其增强/沉默活性。RN46A中的某些等位基因的转录活性甚至显著低于其他等位基因。我们还研究了这些等位基因、增强/沉默活动和情绪障碍事件之间的关系。心境障碍患者的等位基因频率和等位基因频率与对照组无显著差异。

Serotonin transporter (5-HTT) is involved in the presynaptic reuptake of serotonin to terminate and modulate serotonergic neurotransmission. The 5-HTT is the site of action of widely-used reuptake-inhibiting antidepressants. Therefore, a dysfunction of 5-HTT has been implicated in the etiology of psychiatric disorders such as mood and anxiety disorders. The human 5-HTT gene has been cloned and mapped on chromosome 17q11.1-q12. Recently, a polymorphism has been identified in the region for transcriptional control of the gene (5-HTTLPR), which consists of different length of the repetitive sequence containing GC-rich, 20〜23-bp-long repeat elements in the upstream regulatory region of the gene. A deletion/insertion in the 5-HTTLPR creates a short (S) allele and a long (L) allele (14- and 16-repeat alleles), which alters the promoter activity. We analyzed the 5-HTTLPR in detail and identified ten novel sequences, in addition to those previously reported, and demonstrated the difference in their distribution in Japanese and Caucasian individuals. The enhancer/silencer activities of the SHTTLPR-sequences with the pGL-3 promoter vector were measured in several cell lines including RN46A, which is derived from mouse raphe nucleus. Some alleles showed even significantly lower transcription activities than other alleles in RN46A. We also examined relationship between these alleles, enhancer/silencer activities and incidents of mood disorder. The genotypic and allelic frequencies were not significantly different between the mood disorder patients and the control group.