Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.
Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.
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候选人类癫痫相关基因的斑马鱼模型提供了过度兴奋的证据。
DOI：
10.1101/2024.02.07.579190
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Poduri,Annapurna
中科院分区：
文献类型：
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作者：
LaCoursiere,ChristopherMark;Ullmann,JeremyFP;Koh,HyunYong;Turner,Laura;Baker,CristinaM;Robens,Barbara;Shao,Wanqing;Rotenberg,Alexander;McGraw,ChristopherM;Poduri,Annapurna
由于下一代测序和大型全基因组关联研究的进展，数百种新的候选人类癫痫相关基因已被确定，但建立遗传病因需要功能验证。我们生成了一份约2,200个候选癫痫相关基因的列表，其中48个被开发成稳定功能丧失（LOF）斑马鱼模型。在这48例中，有5例（arfgef1, kcn2,kcnv1，ubr5和wnt8b）存在癫痫样行为的证据。进一步的表征通过电生理inkd2和wnt8突变体提供了癫痫样活动的证据。此外，arfgef1和wnt8突变体显示出幼虫动物视神经顶盖中抑制性中间神经元数量的减少。此外，RNA测序（RNA-seq）揭示了突变系之间的趋同转录异常，这与它们的发育缺陷和过度兴奋表型一致。这些斑马鱼模型提供了最有力的实验证据，支持arfgef1、KCND2和wnt8在人类癫痫中的作用，并进一步证明了该模型系统在评估人类癫痫候选基因方面的实用性。
Hundreds of novel candidate human epilepsy-associated genes have been identified thanks to advancements in next-generation sequencing and large genome-wide association studies, but establishing genetic etiology requires functional validation. We generated a list of >2,200 candidate epilepsy-associated genes, of which 48 were developed into stable loss-of-function (LOF) zebrafish models. Of those 48, evidence of seizure-like behavior was present in 5 (arfgef1,kcnd2,kcnv1,ubr5, andwnt8b). Further characterization provided evidence for epileptiform activity via electrophysiology inkcnd2andwnt8bmutants. Additionally,arfgef1andwnt8bmutants showed a decrease in the number of inhibitory interneurons in the optic tectum of larval animals. Further, RNA sequencing (RNA-seq) revealed convergent transcriptional abnormalities between mutant lines, consistent with their developmental defects and hyperexcitable phenotypes. These zebrafish models provide strongest experimental evidence supporting the role ofARFGEF1,KCND2, andWNT8Bin human epilepsy and further demonstrate the utility of this model system for evaluating candidate human epilepsy genes.