title: Novel evidence of the involvement of calreticulin in major psychiatric disorders.
abstract: Calreticulin (CALR) is a multi-functional protein that is strictly conserved across species. Two mRNA transcripts have been recognized for the CALR gene in humans, which use a common promoter sequence. We have recently reported mutations in the CALR promoter that co-occur with psychosis. One of those mutations at -220A increases gene expression in human BE(2)-C and HEK-293 cell lines. This mutation is the first instance of a functional cognition-deficit mutation reversing a human gene promoter to the primitive type. In the current study, we analyzed the effect of the most widely-used mood-stabilizing drug, valproic acid (VPA), on nucleotide -220 in two neuronal cell lines, LAN-5 and N2A. Remarkably, VPA increased gene expression in the cells with the wild-type -220C construct, whereas a dramatic decrease in gene expression was observed in the cell lines with the mutant construct (p<0.000004 and p<0.016, respectively). We also sequenced the 600-bp CALR promoter, and the highly conserved intron 1 sequence in an independent sample of patients afflicted with major psychiatric disorders and controls. A new case of major depressive disorder with psychotic features with the -220A mutation was identified. A novel 1-bp insertion was also detected in intron 1 at IVSI-310, in a case of amphetamine-induced psychosis. As for the psychosis-linked CALR promoter mutations identified to-date, the IVSI mutation was not detected in the control pool. This mutation creates a RREB-1 transcription factor binding site within the first intron. Our present findings identify the site of action of VPA in the CALR promoter, and introduce a novel mutation in a case of substance-induced psychosis in the first intron of CALR.
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. rahaannn@yahoo.com
authors.forename: M
authors.initials: M
authors.lastname: Ohadi
authors.forename: A
authors.initials: A
authors.lastname: Mirabzadeh
authors.forename: E
authors.initials: E
authors.lastname: Esmaeilzadeh-Gharehdaghi
authors.forename: M
authors.initials: M
authors.lastname: Rezazadeh
authors.forename: S
authors.initials: S
authors.lastname: Hosseinkhanni
authors.forename: M
authors.initials: M
authors.lastname: Oladnabi
authors.forename: S Ghasemi
authors.initials: SG
authors.lastname: Firouzabadi
authors.forename: H
authors.initials: H
authors.lastname: Darvish
mesh_terms: D018692:Antimanic Agents / Q000494:pharmacology*; D037282:Calreticulin / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D037282:Calreticulin; D014635:Valproic Acid