Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy

Dravet syndrome (DS) is a developmental and epileptic encephalopathy that results from mutations in the Na v 1.1 sodium channel encoded by SCN1A . Most known DS-causing are coding regions of , but we recently identified several disease-associated intron 20 within or near to cryptic evolutionarily conserved “poison” exon, 20N, whose inclusion predicted lead transcript degradation. However, it not clear how these variants alter expression DS pathophysiology an organismal context, nor exon 20N regulated tissue-specific context. We address those questions here generating animal model our index case, NM_006920.4(SCN1A):c.3969+2451G>C, using gene editing create orthologous mutation laboratory mice. Scn1a heterozygous knock-in (+/ KI ) mice exhibited ~50% reduction brain mRNA protein levels, together with characteristics observed other mouse models, including premature mortality, seizures, hyperactivity. In tissue adult +/+ animals, quantitative RT-PCR assays indicated ~1% included while +/KI ~5-fold increase extent inclusion. investigated during normal fetal development RNA-seq data discovered levels were ~70% at E14.5, declining progressively ~10% postnatally. A similar pattern exists for homologous 1.6, Scn8a For both genes, there inverse relationship between level functional poison Taken together, findings suggest usage strategy regulate development, recapitulating fetal-like splicing cause reduced encephalopathy.