Mutations 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 were examined and a polymorphic C-G change located at −1017 bp 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. A protein that binds to the DNA at the −1017 locus has been identified. Any such proteins that bind to the DNA at this region 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.

1 - 6 . (canceled)  
     
     
         7 . A method for detecting depression and related mental illnesses comprising the steps of: 
 selecting primers to amplify a DNA region from the repressor of the 5-HT1A receptor gene (SEQ ID NO: 1) in a test sample;    amplifying the DNA region from the repressor of the 5-HT1A receptor gene in the test sample; and    determining the sequence of the DNA region from the repressor of the 5-HT1A receptor gene, whereby identification of a mutation in said DNA region consisting of a C-G substitution mutation at position 2422 of SEQ ID NO:1, is indicative of depression and related mental illness.    
     
     
         8 . A method of identifying a protein which binds to a DNA region from the repressor of the 5-HT1A receptor gene comprising the steps of: 
 using an oligonucleotide from the repressor of the 5-HT1A receptor gene to screen a cDNA expression library;    identifying proteins that bind to the oligonucloetide; and    cloning cDNA's of the proteins that bind the oligonucleotide.