Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function

Abstract

We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B (NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of voltage-gated sodium (Na_V ) channel function, we examined the effects of human SCN1B^R46C (β1^R46C ), SCN1B^R60C (β1^R60C ), and SCN1B^V158M (β1^V158M ) on the three predominant brain Na_V channel subtypes Na_V 1.1 (SCN1A), Na_V 1.2 (SCN2A), and Na_V 1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance-voltage relationships (Na_V 1.2/β1^R46C , Na_V 1.2/β1^R60C , Na_V 1.6/β1^R46C , Na_V 1.6/β1^R60C , and Na_V 1.6/β1^V158M ) and channel availability (Na_V 1.1/β1^R46C , Na_V 1.1/β1^V158M , Na_V 1.2/β1^R46C , Na_V 1.2/β1^R60C , and Na_V 1.6/β1^V158M ), and detected a slower recovery from fast inactivation for Na_V 1.1/β1^V158M . Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal Na_V channel function in the brain, which may contribute to EIEE52.

Keywords: SCN1B; EIEE52; developmental and epileptic encephalopathy; early infantile epileptic encephalopathy 52; voltage-gated sodium channel.