Reversion of the human calreticulin gene promoter to the ancestral type as a result of a novel psychosis-associated mutation

Development-dependent, tissue-specific expression of the calreticulin (CALR) gene in the gray matter coincides with the expression of psychoses phenotypes. We have recently reported instances of mutations within the core promoter sequence of the gene in schizoaffective disorder. In view of the mounting evidence on the genetic overlap in the psychiatric spectrum, we investigated this gene in a spectrum of patients afflicted with schizophrenia, schizoaffective disorder and major affective disorder. We found that a unique mutation at nucleotide -220 from the transcription start site, located at a conserved genomic block in the promoter region of the gene, co-occurs with the spectrum of psychoses (p<0.005). This mutation reverts the human promoter sequence to the ancestral type observed in chimpanzee, mouse, and several other species, implying that the genomic block harboring nucleotide -220 may be involved in the evolution of human-specific higher-order functions of the brain (e.g. language, conceptual thinking, and judgment), that are ubiquitously impaired in psychoses. We propose that CALR is not only a promising candidate in the spectrum of psychoses, but also, a gene that may be important in the human-unique brain processes.