Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations inSCN1A, encoding voltage-gated sodium channel Na_v1.1 α subunits. Sodium channels are modulated by β1 subunits, encoded bySCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation inSCN1B(p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na_v1.1 α subunits. Because the patient was homozygous for the mutation, these data suggest a functionalSCN1Bnull phenotype. To understand the consequences of the lack of β1 cell surface expressionin vivo, hippocampal slice recordings were performed inScn1b^−/−versusScn1b^+/+mice.Scn1b^−/−CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to theScn1a^+/−model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. WhereasScn1b^−/−mice seize spontaneously, the seizure susceptibility ofScn1b^+/−mice was similar to wild type, suggesting that, like the parents of this patient, one functionalSCN1Ballele is sufficient for normal control of electrical excitability. We conclude thatSCN1Bp.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.

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