Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?
Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?
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DOI：
10.1007/s00335-014-9509-z
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发表时间：
2014-06
期刊：
影响因子：
2.5
通讯作者：
Neubig, Richard R.
中科院分区：
文献类型：
--
作者：
Kehrl, Jason M.;Sahaya, Kinshuk;Dalton, Hans M.;Charbeneau, Raelene A.;Kohut, Kevin T.;Gilbert, Kristen;Pelz, Madeline C.;Parent, Jack;Neubig, Richard R.
G蛋白偶联受体强烈调节神经元兴奋性，但很少有证据表明G蛋白在遗传性癫痫中的作用机制。最近，4例癫痫性脑病（EIEE 17）患者被发现存在脑中最丰富的G蛋白GNAO 1突变，但这种效应的机制尚不清楚。GNAO 1基因产物Gαo负调节神经递质的释放。在这里，我们报告了一个占主导地位的Gnao 1相关的癫痫发作和猝死的小鼠模型。我们引入了基因组功能获得性敲入突变（Gnao 1 +/G184 S），其防止G蛋白信号传导蛋白的调节子关闭Go。这导致罕见的癫痫发作，15至40周龄之间的应变依赖性死亡，以及发作间期癫痫样放电频率显著增加。在C57 BL/6 J背景上的突变体也对戊四唑（PTZ）点燃具有更快的敏感性。在129 SvJ小鼠品系中，过早致死和PTZ点燃效应均受到抑制。我们已经在17号染色体上定位了一个129 S衍生的修饰基因座（在41-70 MB区域内），作为G蛋白癫痫发作的修饰基因（Mogs 1）。我们的小鼠模型提示了一种新定义的癫痫性脑病（EIEE 17）子集的新功能获得机制。此外，它揭示了一种新的癫痫易感性修饰剂Mogs 1，其对人类癫痫的复杂遗传学以及癫痫猝死具有影响。本文的在线版本（doi：10.1007/s 00335 -014-9509-z）包含补充材料，可供授权用户使用。
G protein-coupled receptors strongly modulate neuronal excitability but there has been little evidence for G protein mechanisms in genetic epilepsies. Recently, four patients with epileptic encephalopathy (EIEE17) were found to have mutations in GNAO1, the most abundant G protein in brain, but the mechanism of this effect is not known. The GNAO1 gene product, Gαo, negatively regulates neurotransmitter release. Here, we report a dominant murine model of Gnao1-related seizures and sudden death. We introduced a genomic gain-of-function knock-in mutation (Gnao1+/G184S) that prevents Go turnoff by Regulators of G protein signaling proteins. This results in rare seizures, strain-dependent death between 15 and 40 weeks of age, and a markedly increased frequency of interictal epileptiform discharges. Mutants on a C57BL/6J background also have faster sensitization to pentylenetetrazol (PTZ) kindling. Both premature lethality and PTZ kindling effects are suppressed in the 129SvJ mouse strain. We have mapped a 129S-derived modifier locus on Chromosome 17 (within the region 41–70 MB) as a Modifer of G protein Seizures (Mogs1). Our mouse model suggests a novel gain-of-function mechanism for the newly defined subset of epileptic encephalopathy (EIEE17). Furthermore, it reveals a new epilepsy susceptibility modifier Mogs1 with implications for the complex genetics of human epilepsy as well as sudden death in epilepsy. The online version of this article (doi:10.1007/s00335-014-9509-z) contains supplementary material, which is available to authorized users.
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