De novo BK channel mutation causes epilepsy by regulating voltage-dependent, but not calcium-dependent, activation

Epilepsy is one of the most common neurological diseases. Here we report the first de novo mutation in the BK channel (p.N995S) that causes epilepsy in two independent families. The p.N995S mutant channel showed a markedly increased macroscopic potassium current mediated by increases in both channel open probability and channel open dwell time. Mutation p.N995S affects the voltage-activation pathway of BK channel, but does not affect the calcium sensitivity. Paxilline blocks potassium currents from both WT and mutant BK channels. We also identified two variants of unknown significance, p.E656A and p.N1159S in epilepsy patients. However, they do not affect BK channel functions, therefore, are unlikely to be a cause of disease. These results expand the BK channelopathy to a more common disease of epilepsy, suggest that the BK channel is a drug target for treatment of epilepsy, and highlight the importance of functional studies in the era of precision medicine.