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A de novo nonsense mutation of STXBP1 causes early-onset epileptic encephalopathy
Epilepsy & Behavior ( IF 2.3 ) Pub Date : 2021-08-12 , DOI: 10.1016/j.yebeh.2021.108245
Guihai Suo 1 , Xing Cao 2 , Yuqin Zheng 2 , Haiying Li 2 , Qi Zhang 3 , Jihong Tang 4 , Youjia Wu 2
Affiliation  

Mutations in syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to multiple neurodevelopmental disorders, including severe early-onset epileptic encephalopathies (EOEEs). A de novo nonsense mutation of STXBP1 (c. 863G > A, p. W288X) was found in a patient diagnosed with EOEE at the age of 17 days. The electroencephalogram (EEG) showed sharp waves and spikes, while brain magnetic resonance imaging was normal. We generated a zebrafish EOEE model by overexpressing mutant STXBP1(W288X) and studied the behavioral changes further to understand the mechanism of W288X mutation in epileptogenesis. In addition, effective antiepileptic drugs were screened in the zebrafish model. Zebrafish STXBP1 homologs were highly conserved and prominently expressed in the larval zebrafish brain. The Tg(hSTXBP1W288X) zebrafish larvae exhibited hyperactivity compared with the wild-type (WT) controls. The expression of STXBP1 decreased during the development course from 1 to 5 days post fertilization. Spontaneous seizures and increased c-fos expression were observed in the mutant zebrafish larvae. The susceptibility of Tg(hSTXBP1W288X) zebrafish to pentylenetetrazol challenge also dramatically increased. Levetiracetam, clonazepam, and topiramate showed antiepileptic effects in the Tg(hSTXBP1W288X) larvae to different extents. Our findings in the newly generated mutant line of zebrafish suggested that zebrafish recapitulated clinical phenotypes associated with human STXBP1 mutation, which provided an appropriate in vivo model for epilepsy research.



中文翻译:

STXBP1 的从头无义突变导致早发性癫痫性脑病

突触结合蛋白 1、STXBP1(也称为 MUNC18-1)的突变与多种神经发育障碍有关,包括严重的早发性癫痫性脑病 (EOEE)。在 17 天时诊断为 EOEE 的患者中发现了 STXBP1 的从头无义突变(c. 863G > A,p . W288X 。脑电图(EEG)显示尖波和尖峰,而脑磁共振成像正常。我们通过过表达突变体STXBP1(W288X)生成了斑马鱼 EOEE 模型,并进一步研究了行为变化,以了解 W288X 突变在癫痫发生中的机制。此外,在斑马鱼模型中筛选出有效的抗癫痫药物。斑马鱼STXBP1同源物在幼虫斑马鱼脑中高度保守并显着表达。与野生型 (WT) 对照相比,Tg( hSTXBP1 W288X ) 斑马鱼幼虫表现出多动症。STXBP1的表达在受精后1至5天的发育过程中下降。在突变斑马鱼幼虫中观察到自发性癫痫发作和增加的 c-fos表达。Tg( hSTXBP1 W288X ) 斑马鱼对戊四唑挑战的敏感性也显着增加。左乙拉西坦、氯硝西泮和托吡酯在 Tg( hSTXBP1 W288X ) 中显示出抗癫痫作用) 不同程度的幼虫。我们在新生成的斑马鱼突变系中的发现表明,斑马鱼概括了与人类STXBP1突变相关的临床表型,这为癫痫研究提供了适当的体内模型。

更新日期:2021-08-12
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