Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment

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 Nav1.1. 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 Nav1.1 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 Nav1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

Keywords: Chromatin architecture; Dravet syndrome; Na(v)1.1; Neural differentiation; Neurodevelopment; SCN1A; iPSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chromatin Assembly and Disassembly / genetics*
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / metabolism
  • GABAergic Neurons / metabolism*
  • Haploinsufficiency
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • Neural Stem Cells / metabolism
  • Neurogenesis / genetics*
  • Neuronal Plasticity / physiology
  • Oxidative Stress / physiology
  • Transcriptome


  • NAV1.1 Voltage-Gated Sodium Channel
  • SCN1A protein, human