Pharmacological rescue of mutated K v 3.1 ion-channel linked to progressive myoclonus epilepsies.

Progressive myoclonus epilepsies (PMEs) constitute a cluster of inherent, genetically diverse, rare seizure disorders characterized by ataxia, tonic-clonic seizures, and action myoclonus. Recently, a mutation in the KCNC1 gene (Arg320His) was described in a group of PME patients. The KCNC1 gene encodes the Kv 3.1 potassium ion channel responsible for the rapid repolarization of the membrane potential following action potential firing in fast spiking GABAergic interneurons (FSI), thereby enabling high firing frequency. In the present study, we demonstrate that the Arg320His mutation cause a reduction in the Kv 3.1 current amplitude and acts in a dominantly negative fashion. The mutation profoundly affects channel activation and deactivation kinetics, and we further find that it impairs recruitment of the Kv 3.1 channel to the plasma membrane. The Kv 3 activating compound, RE01, partly rescues the electrophysiological deficit, suggesting that pharmacological activation of Kv 3.1 activity might be a feasible approach for treatment of this cohort of PME patients.