Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
Chalfont Centre for Epilepsy, Bucks SL9 0RJ, UK.
Hum Mol Genet. 2023 May 5;32(10):1753-1763. doi: 10.1093/hmg/ddad015.
Pathogenic variations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy phenotypes, including Dravet syndrome, febrile seizures (FS) and genetic epilepsy with FS plus. Phenotypic heterogeneity is a hallmark of SCN1A-related epilepsies, the causes of which are yet to be clarified. Genetic variation in the non-coding regulatory regions of SCN1A could be one potential causal factor. However, a comprehensive understanding of the SCN1A regulatory landscape is currently lacking. Here, we summarized the current state of knowledge of SCN1A regulation, providing details on its promoter and enhancer regions. We then integrated currently available data on SCN1A promoters by extracting information related to the SCN1A locus from genome-wide repositories and clearly defined the promoter and enhancer regions of SCN1A. Further, we explored the cellular specificity of differential SCN1A promoter usage. We also reviewed and integrated the available human brain-derived enhancer databases and mouse-derived data to provide a comprehensive computationally developed summary of SCN1A brain-active enhancers. By querying genome-wide data repositories, extracting SCN1A-specific data and integrating the different types of independent evidence, we created a comprehensive catalogue that better defines the regulatory landscape of SCN1A, which could be used to explore the role of SCN1A regulatory regions in disease.
钠离子电压门控通道α亚基 1（SCN1A）基因中的致病变异可导致多种癫痫表型，包括 Dravet 综合征、热性惊厥（FS）和伴有 FS 的遗传性癫痫。SCN1A 相关癫痫的表型异质性是其特征之一，但其病因尚不清楚。SCN1A 非编码调控区的遗传变异可能是一个潜在的致病因素。然而，目前对 SCN1A 调控景观的认识还很不全面。在这里，我们总结了 SCN1A 调控的现有知识状态，详细介绍了其启动子和增强子区域。然后，我们通过从全基因组数据库中提取与 SCN1A 基因座相关的信息，整合了目前可用的 SCN1A 启动子数据，并明确界定了 SCN1A 的启动子和增强子区域。此外，我们还探索了差异 SCN1A 启动子使用的细胞特异性。我们还回顾和整合了现有的人类大脑衍生增强子数据库和小鼠衍生的数据，为 SCN1A 大脑活性增强子提供了全面的计算开发总结。通过查询全基因组数据库，提取 SCN1A 特异性数据并整合不同类型的独立证据，我们创建了一个更全面的目录，更好地定义了 SCN1A 的调控景观，这可以用来探索 SCN1A 调控区域在疾病中的作用。
