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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 NaV1.1, which is abundant in the central nervous system. Dravet syndrome can be caused by either gain-of-function mutation or loss of function in NaV1.1, making it necessary to characterize each novel mutation. Here we use a combination of patch-clamp recordings and immunocytochemistry to characterize the first known NH2-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 NaV1.1 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 NH2-terminus of NaV1.1. We studied M72dup using patch-clamp electrophysiology and immunocytochemistry. M72dup causes a decrease in membrane expression of NaV1.1 and overall loss of function, consistent with the role of the NH2-terminal region in membrane trafficking of NaV1.1.

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.

Voltage gated sodium channels (VGSC) are implicated in cancer cell invasion and metastasis. However, the mechanism by which VGSC increase cell invasiveness and probability of metastasis is still unknown. In this review we outline lesser known functions of VGSC outside of action potential propagation, and the current understanding of the effects of VGSC in cancer. Finally, we discuss possible downstream effects of VGSC activation in cancer cells. After extensive review of the literature, the most likely role of VGSC in cancer is in the invadopodia, the leading edge of metastatic cancer cells. Sodium gradients are used to drive many biological processes in the body, and invadopodia may be similar. The function of the sodium hydrogen exchanger (NHE) and sodium calcium exchanger (NCX) are driven by sodium gradients. Voltage gated calcium channels, activated by membrane depolarization, are also capable of becoming activated in response to VGSC activity. Changes to hydrogen ion exchange or calcium handling have functional consequences for invadopodia and would explain the relationship between VGSC expression and invasiveness of cancer cells.