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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia
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Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia

机译：钙调神经磷酸酶途径的遗传分析确定了EGR基因家族的成员，特别是EGR3，是精神分裂症的潜在易感性候选者

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The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. 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. Four of these genes (PPP3CC, EGR2. EGR3. and EGR4) showed nominally significant association with schizophrenia. 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. These findings raise a potentially important rote for EGR genes in schizophrenia pathogenesis. 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. One of these, IVS1 + 607A→G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene.
机译：钙调神经磷酸级联是神经元信号转导的核心，并且该网络中的基因是有趣的候选精神分裂症易感基因。为了复制和扩展我们先前报道的编码钙调神经磷酸酶催化的γ-亚基的PPP3CC基因与精神分裂症之间的关联，我们使用124个日本精神分裂症谱系对14个钙调神经磷酸酶相关候选基因的84个SNP进行了遗传关联。这些基因中的四个（PPP3CC，EGR2，EGR3和EGR4）名义上与精神分裂症显着相关。在脑后研究中，EGR1。在精神分裂症患者的前额叶皮层中，EGR2和EGR3转录物被下调，但在双相情感障碍患者中则不。这些发现为精神分裂症发病机理中的EGR基因提供了潜在的重要参考。由于EGR3是一个有吸引力的候选基因，因为它的染色体位置靠近PPP3CC（在8p21.3内），并且与多巴胺，谷氨酸和神经调节蛋白的功能相关，因此我们通过对整个EGR3基因组间隔重新测序来扩展我们的分析，并检测到15个SNP。其中之一，IVS1 + 607A→G SNP，显示出最强的疾病关联证据，已在1,140个独立的病例对照样本中得到证实。体外启动子测定检测到该SNP可能的表达调节作用。这些发现支持以前的钙调磷酸酶信号转导与精神分裂症发病机理的遗传关联，并将EGR3鉴定为令人信服的易感基因。

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