Distinct functional alterations in SCN8A epilepsy mutant channels

Abstract

SCN8A is a novel causal gene for early infantile epileptic encephalopathy. It is well accepted that gain-of-function mutations in SCN8A underlie the disorder, but the remarkable heterogeneity of its clinical presentation and poor treatment response demand for better understanding of the disease mechanisms. Here, we characterize a new epilepsy-related SCN8A mutation, R850Q, in human Nav1.6. We show that it is a gain-of-function mutation, with a hyperpolarizing shift in voltage dependence of activation, a 2-fold increase of persistent current and a slowed decay of resurgent current. We systematically compare its biophysics with three other SCN8A epilepsy mutations, T767I, R1617Q and R1872Q, in the human Nav1.6 channel. Although all of these mutations are gain-of-function, the mutations affect different aspects of channel properties. One commonality we discovered is an alteration of resurgent current kinetics, but the mechanisms by which resurgent currents are augmented is not yet clear for all of the mutations. Computational simulations predict increased excitability of neurons carrying these mutations with differential enhancement by open channel block.