Channelopathy-Associated Epilepsy Research Center

通道病，特别是涉及电压门控钠 (NaV) 和钾 (KV) 通道基因的通道病， 导致具有不同临床严重程度的多种癫痫综合征。此外，NaV 和 KV 通道是许多已批准和在研抗惊厥药物的重要靶点。在众多之中 与癫痫相关的基因，编码 NaV 和 KV 通道的基因具有最高的累积变异 负担（人类基因突变数据库中超过 2,000 个变异），约占全部变异的三分之一 报道了与癫痫和相关神经发育障碍相关的遗传变异。但是 区分致病性和良性变异并建立基因型-表型关系已成为 由于研究和发现的变体数量爆炸式增长，变得越来越具有挑战性 临床医学。通道病相关癫痫代表了应对挑战的独特机会 变异注释，因为这些蛋白质存在完善的体外功能测定范例， 加上有关它们对神经元功能和药物反应的贡献的广泛知识。 我们建议建立一个多机构和跨学科的通道病相关癫痫 研究中心将把高通量技术与高含量的人类神经元和 动物模型系统。该中心将由三个综合研究项目和两个科学核心组成 涉及学术界和工业界科学家的协同合作。项目一将进行大规模 编码电压门控离子通道的基因变异的功能评估经常与 单基因癫痫，然后与修订后的变异分类一起整理研究结果。项目2将 使用常规方法研究通道病相关癫痫的人类神经元模型 电生理方法和特别创新的工业光遗传学方法（Optopatch） 以单细胞精度同时刺激和记录数百个神经元的数据。项目3将 开发和研究新的通道病相关癫痫小鼠模型并比较变异离子 跨模型系统的通道功能障碍。项目将通过与变体优先级的合作得到帮助 和管理核心以及诱变和细胞表达核心。我们中心的一个主要目标是确定 非神经元细胞模型可以在多大程度上预测神经元和大脑中离子通道变异的影响。我们的 总体目标是促进我们对功能后果的理解的变革性进步 通道病相关癫痫的遗传变异，并实现向基因/变异的范式转变 基于癫痫的分类学，与传统的临床分类方案相协调，同时指导 实施精准医疗。

Channelopathies, particularly those involving voltage-gated sodium (NaV) and potassium (KV) channel genes, are responsible for a variety of epilepsy syndromes having diverse clinical severity. Further, NaV and KV channels are important targets for many approved and investigational anticonvulsant drugs. Among the many genes associated with epilepsy, those encoding NaV and KV channels have the highest cumulative variant burden (>2,000 variants in the Human Gene Mutation Database), accounting for approximately one third of all reported genetic variants associated with epilepsy and related neurodevelopmental disorders. But differentiating pathogenic from benign variants and establishing genotype-phenotype relationships has become increasingly challenging because of explosive growth in the number of variants discovered in research and clinical medicine. Channelopathy-associated epilepsies represent unique opportunities to meet the challenge of variant annotation because well-established in vitro functional assay paradigms exist for these proteins, coupled with extensive knowledge regarding their contributions to neuronal function and drug response. We propose to create a multi-institutional and interdisciplinary CHANNELOPATHY-ASSOCIATED EPILEPSY RESEARCH CENTER that will combine high-throughput technologies with high-content human neuron and animal model systems. The Center will consist of three integrated research projects and two scientific cores involving a synergistic mixture of academic and industry scientists. Project 1 will conduct a large-scale functional evaluation of variants in genes encoding voltage-gated ion channels frequently associated with monogenic epilepsy, then curate findings in tandem with revised variant classifications. Project 2 will investigate human neuron models of channelopathy-associated epilepsy using conventional electrophysiological methods and an especially innovative, industrial optogenetic approach (Optopatch) to stimulate and record data from hundreds of neurons simultaneously with single-cell precision. Project 3 will develop and investigate new mouse models of channelopathy-associated epilepsy and compare variant ion channel dysfunction across model systems. Projects will be aided by collaboration with a Variant Prioritization and Curation Core and a Mutagenesis and Cell Expression Core. A key objective of our Center is to determine to what extent non-neuronal cell models can predict effects of ion channel variants in neurons and brain. Our overarching goal is to promote transformative advances in our understanding of the functional consequences of genetic variants in channelopathy-associated epilepsy, and to enable a paradigm shift to a gene/variant- based taxonomy of epilepsy that harmonizes with traditional clinical classification schemes while guiding the implementation of precision medicine.