Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia
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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DOI：
10.1073/pnas.0610765104
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发表时间：
2007-02-20
影响因子：
11.1
通讯作者：
Yoshikawa, Takeo
中科院分区：
文献类型：
--
作者：
Yamada, Kazuo;Gerber, David J.;Yoshikawa, Takeo
钙调神经磷酸酶级联反应是神经元信号转导的核心，该网络中的基因是精神分裂症易感基因的有趣候选者。为了复制和扩展我们先前报道的PPP 3CC基因（编码钙调神经磷酸酶催化γ亚基）与精神分裂症之间的关联，我们使用124个日本精神分裂症家系检查了来自14个钙调神经磷酸酶相关候选基因的84个SNIPS。其中四个基因（PPP 3CC，EGR 2，EGR 3和EGR 4）与精神分裂症有显著相关性。在一项死后大脑研究中，精神分裂症患者的前额叶皮层中的EGR 1、EGR 2和EGR 3转录物被下调，但双相情感障碍患者则没有。这些发现提出了一个潜在的重要作用，EGR基因在精神分裂症的发病机制。由于EGR 3是一个有吸引力的候选基因，基于其染色体位置接近8p21.3内的PPP 3CC及其与多巴胺、谷氨酸和神经调节蛋白信号传导的功能联系，我们通过对整个EGR 3基因组间隔进行重新测序来扩展我们的分析，并检测到15个SNP。其中IVS 1 + 607 A-> G SNP显示出疾病关联的最强证据，这在1，140个独立病例对照样本中得到证实。体外启动子试验检测到该SNP可能的表达调节作用。这些发现支持了先前改变的钙调磷酸酶信号传导与精神分裂症发病机制的遗传关联，并将EGR 3确定为一个引人注目的易感基因。
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 gamma-subunit, and schizophrenia, we examined 84 SNIPS 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 role 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.