Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome

Dravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ~20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic comorbidities of a novel preclinical Dravet mouse model harboring this nonsense Scn1a mutation. Heterozygous Scn1a R613X mutation on a mixed C57BL/6J:129S1/SvImJ background exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, mimicking some non-epileptic Dravet-associated comorbidities. Conversely, Scn1aWT/R613X mice on the pure 129S1/SvImJ background had a normal life span and were easy to breed. Homozygous Scn1aR613X/R613X mice died before P16. Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reduced Scn1a mRNA and Nav1.1 protein levels to ~50% in heterozygous Scn1aWT/R613X mice, with marginal expression in homozygous Scn1aR613X/R613X mice. Together, we introduce a novel Dravet model carrying the R613X Scn1a nonsense mutation that can. be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated with SCN1A nonsense mutations in Dravet.