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

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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.