We previously reported a G>C point mutation located at position -48 within the calreticulin gene core promoter in one individual suffering from paranoid schizophrenia that has also been diagnosed with affective disorder. However, a putative bona fide functional link between this mutation in the calreticulin gene and schizoaffective disorder has remained speculative. We have carried out calreticulin genotyping and psychiatric examination of all available members of the family of the proband and found that three more members carry the -48G>C mutation. Remarkably, two of them develop the disease with an onset and progression that are virtually identical. The third person, too young to have developed fully the disease, nevertheless displays the same symptoms as her affected relatives had at the same early age. Furthermore, transcriptional analysis of the calreticulin promoter in rat cortical neurons shows aberrant increase in transcription in the presence of the -48G>C mutation, both at basal levels and in the presence of valproate and lithium. Our results point to a previously unknown causal role for dysregulation of calreticulin homeostasis in schizoaffective disorder by both genetic and functional analyses, and shed new light on the possible mechanisms of action of valproate and lithium in the treatment of the disease.