Dravet Syndrome (DS) is an epileptic encephalopathy that affects 1 in 30,000 children globally. Characterized by seizure onset after relatively normal early development, 80% of DS cases are monogenic in origin and associated with mutations in the Sodium Channel Type 1 Alpha (SCN1A) gene. SCN1A encodes the voltage-gated sodium channel, Nav1.1, that plays a vital role in action potential generation and propagation in central nervous system neurons. Due to heterogeneity in the causative variant and observed phenotype, there is a need to characterize each novel mutation associated with DS. I characterized the DS-associated mutant N722D using patch-clamp, immunocytochemistry, and computational modelling. N722D does not significantly alter channel activation or inactivation. However, N722D decreases Nav1.1 current density and membrane expression. Supported by information obtained from action potential modelling, I suggest that N722D causes DS due to loss-of-function primarily by altering the trafficking of Nav1.1 to the plasma membrane in neurons.
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Thesis advisor: Ruben, Peter C.
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