An epileptic encephalopathy associated GABRG2 missense mutation leads to preand postsynaptic defects in zebrafish
An epileptic encephalopathy associated GABRG2 missense mutation leads to preand postsynaptic defects in zebrafish
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癫痫性脑病相关的 GABRG2 错义突变导致斑马鱼突触前和突触后缺陷
DOI：
10.1093/hmg/ddab338
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发表时间：
--
影响因子：
3.5
通讯作者：
Dingding Shen
中科院分区：
文献类型：
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作者：
Jing Zhou;Wenpeng Liang;Jie Wang;Juan Chen;Dong Liu;Xin Wang;Youjia Wu3;Qi Zhang;Dingding Shen
γ-氨基丁酸A型（GABAA）受体γ- 2亚基基因GABRG2的突变与多种癫痫综合征有关。在一例早发性癫痫性脑病患者中发现了ingabrg2的Ade novomation （c.T1027C, p.F343L）。过表达突变的人gabrg2 （F343L）亚基的斑马鱼表现出自发的癫痫活动和抽搐行为。在这项研究中，我们证明Tg （hGABRG2F343L）斑马鱼在正常昼夜节律的光期表现出过度活跃，以及药物诱导的运动活动增加。实时荧光定量PCR、全山杂交和western blot结果显示Tg（hGABRG2F343L）斑马鱼gaba受体亚基表达发生改变。此外，对突触蛋白表达和突触超微结构的研究揭示了与gabrg2 （F343L）突变有因果关系的强大突触表型。引人注目的是，Tg（hGABRG2F343L）斑马鱼不仅具有突触后缺陷，而且在突触前水平也表现出意想不到的缺陷。总的来说，我们的Tg（hGABRG2F343L）过表达斑马鱼模型将癫痫性脑病的gaba能模式从通道病扩展到突触病。
Mutations in the γ-aminobutyric acid type A (GABAA) receptor γ2 subunit gene,GABRG2, have been associated with a variety of epilepsy syndromes. Ade novomutation (c.T1027C, p.F343L) inGABRG2was identified in a patient with early onset epileptic encephalopathy. Zebrafish overexpressing mutant humanGABRG2 (F343L)subunits displayed spontaneous seizure activity and convulsive behaviors. In this study, we demonstrated that Tg (hGABRG2F343L) zebrafish displayed hyperactivity during light phase with normal circadian rhythm, as well as increased drug-induced locomotor activity. Real-time quantitative PCR, whole mountin situhybridization and western blotting showed that Tg(hGABRG2F343L) zebrafish had altered expression of GABAAreceptor subunits. Furthermore, investigation of synaptic protein expression and synapse ultrastructure uncovered a robust synaptic phenotype that is causally linked toGABRG2(F343L)mutation. Strikingly, Tg(hGABRG2F343L) zebrafish not only had postsynaptic defects, but also displayed an unanticipated deficit at the presynaptic level. Overall, our Tg(hGABRG2F343L) overexpression zebrafish model has expanded the GABAergic paradigm in epileptic encephalopathy from channelopathy to synaptopathy.