Decreased gene expression activity as a result of a mutation in the calreticulin gene promoter in a family case of schizoaffective disorder.
Accumulating evidence of population association studies support the hypothesis that the high heritability of major psychiatric disorders is a combination of relatively common alleles of modest effect, and rare alleles some with relatively larger effects. We have previously reported low frequency mutations in the proximal promoter of the human calreticulin (CALR) gene that co-occur with the spectrum of major psychiatric disorders. One of those mutations at -205C>T (rs556992558) was detected in an isolate case of schizoaffective disorder. In the current study, the functional implication of mutation -205T is studied in the human neuronal cell lines LAN-5, BE(2)-C and HEK-293. In contrast with other mutations in the promoter region which increase gene expression activity, the -205T mutation significantly decreased gene expression in those cell lines in comparison with the wild-type -205C nucleotide (p < 0.000001, p < 0.0005, and p < 0.017, respectively). Treatment of the cell lines with the mood-stabilizing drug, valproic acid (VPA) resulted in differential gene expression activity in the mutant -205T versus the wild-type -205C construct. VPA increased gene expression activity in both constructs, while a significantly higher expression activity was observed in the mutant construct (p < 0.01), indicative of the creation of a positive effector binding site for VPA as a result of the -205T mutation. We conclude that deviation from normalcy in the level of CALR in either direction is associated with major psychiatric disorders.
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands ; Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
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Farashi
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran ; Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
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Ohadi
Department of Biophysics & Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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Hosseinkhani
Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences and Health Services, Tehran, Iran.
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Darvish
Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
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Mirabzadeh
Calreticulin; Expression; Mutation; Promoter; Psychiatric disorder; Valproic acid