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-羟色胺的重摄取，终止和调节多巴胺能神经传递。5-HTT是广泛使用的抑制再摄取的抗抑郁药的作用部位。因此，5-HTT的功能障碍与精神障碍如情绪障碍和焦虑障碍的病因学有关。人5-HTT基因已被克隆并定位于染色体17q11.1-q12。最近，在该基因的转录调控区（5-HTTLPR）中发现了一种多态性，该多态性由该基因上游调控区中不同长度的重复序列组成，该重复序列含有富含GC的20个23 bp长的重复元件。5-HTTLPR中的缺失/插入产生短（S）等位基因和长（L）等位基因（14和16重复等位基因），其改变启动子活性。我们详细分析了5-HTTLPR，并确定了10个新的序列，除了以前报道的，并证明了他们在日本和高加索人的分布差异。在包括RN 46 A的几种细胞系中测量了具有pGL-3启动子载体的SHTTLR序列的增强子/沉默子活性，RN 46 A来源于小鼠中缝核。在RN 46 A中，一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，增强子/沉默子活动和情绪障碍事件之间的关系。心境障碍组与对照组基因型和等位基因频率差异无统计学意义。

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.