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Lamar, Tyra; Vanoye, Carlos G; Calhoun, Jeffrey; Wong, Jennifer C; Dutton, Stacey B.B; Jorge, Benjamin S; Velinov, Milen; Escayg, Andrew; Kearney, Jennifer A
Neurobiology of disease, 06/2017, Volume: 102Journal Article
Abstract Mutations in voltage-gated sodium channels expressed highly in the brain ( SCN1A , SCN2A , SCN3A , and SCN8A ) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav 1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele ( Scn3a Hyp ) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice ( Scn3a +/ Hyp ) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a +/ Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.
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