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