Case studies in neuroscience: a novel amino acid duplication in the NH2-terminus of the brain sodium channel NaV1.1 underlying Dravet syndrome

Dravet syndrome is a severe form of childhood epilepsy characterized by frequent temperature-sensitive seizures and delays in cognitive development. In the majority (80%) of cases, Dravet syndrome is caused by mutations in the SCN1A gene, encoding the voltage-gated sodium channel Na V 1.1, which is abundant in the central nervous system. Dravet syndrome can be caused by either gain-of-function mutation or loss of function in Na V 1.1, making it necessary to characterize each novel mutation. Here we use a combination of patch-clamp recordings and immunocytochemistry to characterize the first known NH 2 -terminal amino acid duplication mutation found in a patient with Dravet syndrome, M72dup. M72dup does not significantly alter rate of fast inactivation recovery or rate of fast inactivation onset at any measured membrane potential. M72dup significantly shifts the midpoint of the conductance voltage relationship to more hyperpolarized potentials. Most interestingly, M72dup significantly reduces peak current of Na V 1.1 and reduces membrane expression. This suggests that M72dup acts as a loss-of-function mutation primarily by impacting the ability of the channel to localize to the plasma membrane. NEW & NOTEWORTHY Genetic screening of a patient with Dravet syndrome revealed a novel mutation in SCN1A. Of over 700 SCN1A mutations known to cause Dravet syndrome, M72dup is the first to be identified in the NH 2 -terminus of Na V 1.1. We studied M72dup using patch-clamp electrophysiology and immunocytochemistry. M72dup causes a decrease in membrane expression of Na V 1.1 and overall loss of function, consistent with the role of the NH 2 -terminal region in membrane trafficking of Na V 1.1.