POLYMORPHISMS OF THE 5' REGION OF THE HUMAN 5-HT1A GENE, ASSOCIATED PROTEINS OF THE 5' REGION AND A DIAGNOSTIC TEST FOR MAJOR DEPRESSION AND RELATED MENTAL ILLNESSES

摘要

Clinical response to antidepressant compounds correlates with a selectivedown-regulation of presynaptic 5-HT1A receptors in serotonergic raphe neurons.Thusregulation of the 5-HT1A receptor gene could play a crucial role in thetreatment oretiology of major depression. The promoter and repressor activities of thehuman5-HT1A receptor gene have been examined. The analysis of the 5'-flankingregions of the5-HT1A receptor gene has revealed a segment located between about -3438 andabout-393 bp upstream from the initiator ATG that mediates cell-specific repressionof thegene that is greater in cells that do not express the 5-HT1A receptor. Thesequence ofpart of this region in patients with major depression was examined and apolymorphicC-G change located at -1019 bp (numbered earlier as -1017) was identified,which isassociated with major depression. Thus, this sequence can be used as a geneticmarkerfor major depression and related mental illnesses. Proteins that bind to theDNA at the-1019 locus have been identified. Such proteins that bind to this DNA region,forexample the transcription factors NUDR/DEAF-1/suppressin and HES-5, areimportanttargets for the development of therapeutic compounds for the treatment ofmajordepression and related mental illness that involve the serotonin system. Inaddition thepromoter region from about -393 to the initiator ATG displays glucocorticoid-mediatedrepression.