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

Abstract

Clinical response to antidepressant compounds correlates with a selective down-regulation of presynaptic 5-HT1A receptors in serotonergic raphe neurons. Thus regulation of the 5-HT1A receptor gene could play a crucial role in the treatment or etiology of major depression. The promoter and repressor activities of the human 5-HT1A receptor gene have been examined. The analysis of the 5′-flanking regions of the 5-HT1A receptor gene has revealed a segment located between about −3438 and about −393 bp upstream from the initiator ATG that mediates cell-specific repression of the gene that is greater in cells that do not express the 5-HT1A receptor. The sequence of part of this region in patients with major depression was examined and a polymorphic C-G change located at −1019 bp (numbered earlier as −1017) was identified, which is associated with major depression. Thus, this sequence can be used as a genetic marker for major depression and related mental illnesses. Proteins that bind to the DNA at the −1019 locus have been identified. Such proteins that bind to this DNA region, for example the transcription factors NUDR/DEAF-1/suppressin and HES-5, are important targets for the development of therapeutic compounds for the treatment of major depression and related mental illness that involve the serotonin system. In addition the promoter region from about −393 to the initiator ATG displays glucocorticoid-mediated repression.

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