- Study of the mechanism of epilepsy.
- Evaluation of the efficacy of pharmacological agents.
Mutations in the voltage-gated sodium channel SCN1A cause several subtypes of
dominant idiopathic generalized epilepsy (IGE) including Generalized Epilepsy
with Febrile Seizures Plus (GEFS+). GEFS+ is a dominant familial disorder
characterized by febrile (fever-induced) seizures that persist beyond the age of
six and that are often followed by the development of adult epilepsy. Affected
individuals within GEFS+ families often display a wide variety of IGE subtypes
with markedly different ages of onset and severity, suggesting the action of
genetic and/or environmental modifiers. It has been demonstrated that mutations
in SCN1A are responsible for some cases of GEFS+.
Mouse models of GEFS+ have been developed to help elucidate the mechanisms by
which sodium channel dysfunction leads to epilepsy. Two human SCN1A GEFS+
mutations were individually introduced into the mouse SCN1A gene by homologous
recombination (knock-in) in mouse embryonic stem (ES) cells. The mutated ES
cells were used to generate mice with the individual mutations to model human
GEFS+. Heterozygous knock-in mice with the mutations were observed to have
infrequent, spontaneous seizures.