Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia.
Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia.
复制标题
精神分裂症突触脂筏接头基因 PAG1 的测序和表达分析。
DOI：
10.1007/s00702-014-1269-0
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发表时间：
2015
期刊：
影响因子：
3.3
通讯作者：
Maekawa M.
中科院分区：
文献类型：
--
作者：
Balan S;Iwayama Y;Yamada K;Toyota T;Ohnishi T;Toyoshima M;Shimamoto C;Ide M;Iwata Y;Suzuki K;Kikuchi M;Hashimoto T;Kanahara N;Yoshikawa T;Maekawa M.
人们主张突触网络的破坏是精神分裂症等精神疾病的发病机制。大多数参与神经元通讯的突触蛋白都位于脂筏中。这些筏通过聚集相互作用的伙伴，形成协调神经元信号转导的平台。 PAG1 蛋白是脂筏信号簇中的跨膜衔接蛋白，调节 Src 家族激酶 (SFK)，这是调节 N-甲基-d-天冬氨酸 (NMDA) 受体的多种途径的汇聚点。有关 PAG1 和 SFK 的从头错义突变介导精神分裂症患者 NMDA 受体亚基蛋白酪氨酸磷酸化减少的报告，表明其在精神分裂症发病机制中的假定作用。为了评估这一点，我们对日本精神分裂症患者 (n= 1,140) 和对照 (n= 1,140) 的 PAG1 整个编码区进行了重新测序。我们发现了八个错义变体，其中四个以前未报告过。在更大的队列（n = 4,182）中对这些变异进行的病例对照遗传关联分析显示，个体变异与精神分裂症之间既没有统计学上显着的关联，也没有显示患者组中罕见等位基因的负担有任何增加。精神分裂症患者和对照组死后大脑样本中 PAG1 的表达水平也没有显示出显着差异。为了评估 PAG1 在精神分裂症中的精确作用，未来需要更大样本量的研究。
Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates Src family kinases (SFKs), a convergent point for multiple pathways regulatingN-methyl-d-aspartate (NMDA) receptors. Reports of de novo missense mutations inPAG1and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region ofPAG1in Japanese schizophrenia patients (n= 1,140) and controls (n= 1,140). We identified eight missense variants, of which four were previously unreported. Case–control genetic association analysis of these variants in a larger cohort (n= 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels ofPAG1in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role ofPAG1in schizophrenia, future studies with larger sample sizes are needed.