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

摘要

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) (beta 1(R46C)), SCN1B(R60C) (beta 1(R60C)), and SCN1B(V158M) (beta 1(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/beta 1(R46C), Na(V)1.2/beta 1(R60C), Na(V)1.6/beta 1(R46C), Na(V)1.6/beta 1(R60C), and Na(V)1.6/beta 1(V158M)) and channel availability (Na(V)1.1/beta 1(R46C), Na(V)1.1/beta 1(V158M), Na(V)1.2/beta 1(R46C), Na(V)1.2/beta 1(R60C), and Na(V)1.6/beta 1(V158M)), and detected a slower recovery from fast inactivation for Na(V)1.1/beta 1(V158M). Combined with modeling data indicating perturbation-induced structural changes in beta 1, these results suggest that the SCN1B variants reported here can disrupt normal Na-V channel function in the brain, which may contribute to EIEE52.