Tissue-specific expression of the CALR gene in the brain gray matter in late-adolescence and early adulthood coincides with the expression of the psychoses phenotypes. Indeed, increased expression of the chaperone genes in the prefrontal cortex has been reported in patients affected by schizophrenia. We have previously reported cases of psychosis-associated mutations in the CALR gene promoter. One of those mutations at -48 was found to increase the expression of the gene in comparison with the wild type sequence. A recently identified mutation at -220 reverts the conserved block harboring nucleotide -220 to the ancestral type, and has an approximate prevalence of 0.7% in psychoses. In this study, we analyzed the functional implication of this mutation in the human neuroblastoma cell line BE(2)-C, and non-neural Human Embryonic Kidney 293 (HEK-293), and show that the -220A mutation results in a constitutive increase in the expression of the CALR gene (p<0.0003). We checked homology of the first 1000-bp CALR promoter sequence across species, and found that nucleotide -220C is the only human-unique nucleotide in that stretch. The -220A mutation, on the other hand, co-occurs with severe cognition deficit in humans, and is the rule across the species except humans. To our knowledge, the -220A mutation is the first reported instance of a cognition-deficit-associated mutation which reverses a human gene promoter to the primitive type. It may be speculated that, at least the basal transcription of the CALR gene, relating to the proximal promoter region, has been decreased during the process of evolution to humans.
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