Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Box 815, 751 08 Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Box 815, 751 08 Uppsala, Sweden.
Neurobiol Dis. 2019 Dec;132:104583. doi: 10.1016/j.nbd.2019.104583. Epub 2019 Aug 21.
Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the α-subunit of the neuronal sodium channel Na1.1. The syndrome is characterized by age-related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Na1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic inter-neuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Na1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.
德拉维特综合征（DS）是一种早期发病的难治性癫痫，通常由编码神经元钠离子通道 Na1.1 的α亚单位 SCN1A 的从头杂合变异引起。该综合征的特征是癫痫发作、认知能力下降和运动障碍随年龄进展。我们假设 DS 中独特的神经发育特征是由于 Na1.1 单倍不足细胞中分子途径的破坏导致神经分化和成熟受到干扰而引起的。在这里，我们建立了 DS 患者和对照诱导多能干细胞衍生的神经祖细胞（iPSC NPC）和 GABA 能中间神经元（iPSC GABA）细胞。DS 患者的 iPSC GABA 细胞表现出钠离子电流激活的偏移和对诱导氧化应激的反应失调。转录组分析显示，与对照相比，DS 患者的 iPSC NPC 和 DS 患者的 iPSC GABA 细胞中存在染色质结构、有丝分裂进展、神经可塑性和兴奋性相关基因的特异性失调。转录因子 FOXM1 和 E2F1 是组蛋白修饰和细胞周期调节中断途径的正调控因子，在 DS-iPSC GABA 系中明显上调。我们的研究强调了 Na1.1 单倍不足的 GABA 能细胞中染色质重塑的转录变化和中断途径，为重叠的神经发育障碍和其他癫痫提供了一个分子框架。
