The pathogenic N1662D mutation reveals an essential molecular interaction for NaV1.2 channel inactivation

Mutations in the SCN2A gene encoding the Nav1.2 sodium channel can lead to neurodevelopmental disorders including developmental and epileptic encephalopathy (DEE). We studied the N1662D variant associated with severe early-onset DEE. The N1662D mutation, located in the cytoplasmic end of segment 5 of channel domain IV, almost completely prevented fast inactivation without affecting activation. The comparison of wild type and N1662D Nav1.2 channel structures suggested that ambifunctional hydrogen bonding between residues N1662 and Q1494 critically determines fast inactivation.