The expression of calcineurin is particularly enriched in the CNS, where it plays a critical role in the regulation of a diverse array of neuronal functions ( 5, 6). Three mammalian isoforms of CNA and two of CNB have been identified. Calcineurin functions as a heterodimer consisting of a catalytic subunit, calcineurin A (CNA), and regulatory subunit, calcineurin B (CNB). These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene.Ĭalcineurin (protein phosphatase 2B) is a member of the serine/threonine protein phosphatase family and the only known phosphatase that can be activated by Ca 2+ and calmodulin. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. One of these, IVS1 + 607A→G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. Four of these genes ( PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic γ-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes.
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