R1617Q epilepsy mutation slows NaV 1.6 sodium channel inactivation and increases the persistent current and neuronal firing.

The voltage-gated sodium channel NaV 1.6 is the most abundantly expressed sodium channel isoform in the central nervous system. It plays a critical role in saltatory and continuous conduction. Although over 40 NaV 1.6 mutations have been linked to epileptic encephalopathy, only a few have been functionally analysed. In the present study, we characterized a NaV 1.6 mutation (R1617Q) identified in patients with epileptic encephalopathy and intellectual disability. R1617Q substitutes an arginine for a glutamine in the S4 segment of domain IV, which plays a major role in coupling the activation and inactivation of sodium channels. We used patch-clamp to show that R1617Q is a gain-of-function mutation. It is typified by slower inactivation kinetics and a loss of inactivation of voltage-dependence, which result in a 2.5-fold increase in the window current. In addition, sodium currents exhibited an enhanced rate of recovery from inactivation, most likely due to the destabilization of the inactivation state. The alterations in the fast inactivation caused a significant increase in the persistent sodium current. Overexpression of R1617Q in rat hippocampal neurons resulted in an increase in action potential firing activity that was inhibited by riluzole, consistent with the gain-of-function observed. We conclude that the R1617Q mutation causes neuronal hyperexcitability and may result in epileptic encephalopathy.