Abstract
Pathogenic variants in epilepsy genes result in a spectrum of clinical severity. One source of phenotypic heterogeneity is modifier genes that affect expressivity of a primary pathogenic variant. Mouse epilepsy models also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a(+/-)) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a(+/-) mice recapitulate features of Dravet syndrome, including spontaneous seizures, sudden death, and cognitive/behavioral deficits. Scn1a(+/-) mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no spontaneous seizures. In contrast, admixture with C57BL/6J (B6) results in epilepsy and premature lethality. We previously mapped Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for strain-dependent differences in survival. Gabra2, encoding the GABA(A) α2 subunit, was nominated as a candidate modifier at Dsm1. Direct measurement of GABA(A) receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this deletion reestablished normal levels of Gabra2 expression. In this study, we used B6 mice with a repaired Gabra2 allele to evaluate Gabra2 as a genetic modifier of severity in Scn1a(+/-) mice. Gabra2 repair restored transcript and protein expression, increased abundance of α2-containing GABA(A) receptors in hippocampal synapses, and rescued epilepsy phenotypes of Scn1a(+/-) mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome, and support enhancing function of α(2)-containing GABA(A) receptors as treatment strategy for Dravet syndrome.