title: A mutation in the calreticulin gene promoter in a family case of schizoaffective disorder leads to its aberrant transcriptional activation.
abstract: 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.
authors.affiliation: MRC Centre for Neurodegeneration, Department of Neuroscience PO37, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Nunes
authors.forename: Mina
authors.initials: M
authors.lastname: Ohadi
authors.forename: Alireza
authors.initials: A
authors.lastname: Rahimi
authors.forename: Ali
authors.initials: A
authors.lastname: Aghajani
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Antonio
authors.initials: A
authors.lastname: Currais
authors.forename: Salvador
authors.initials: S
authors.lastname: Soriano
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D064032:Calbindin 2; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002648:Child; D005190:Family; D005260:Female; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011618:Psychotic Disorders / Q000235:genetics*; D051381:Rats; D064030:S100 Calcium Binding Protein G / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D064032:Calbindin 2; D002491:Central Nervous System Agents; D018020:Lithium Compounds; D064030:S100 Calcium Binding Protein G; D014635:Valproic Acid