| Voltage-gated sodium channels transfer electrical signals throughout the nervous system and are a target for mutations associated with epilepsy syndromes. Four mutations of countercharge residues in the brain channel SCN2A coding for Nav1.2 have been identified in patients with severe infantile epilepsies. These include N132K, D195G, and E169G in domain I, and E1211K in domain III. In my thesis project, I aimed to functionally characterize these mutations using cut-open voltage clampelectrophysiology to determine how each mutation contributes to the epilepsy phenotype. Interestingly, I observed different effects conferred by each mutation on hNaV1.2 channel function. N132K caused gain of function in hNav1.2, E169G caused loss of function in hNav1.2, and D195G and E1211K caused mixed effects. These characterizations contribute to the knowledge on countercharge function in voltage-gating and in disease and provide a biological basis for potential drug treatment for epilepsy patients with these mutations. |