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Nav1.1 N722D mutant causes Dravet Syndrome through loss-of-function

Resource type
Thesis type
(Thesis) M.Sc.
Date created
2022-09-16
Authors/Contributors
Abstract
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.
Document
Extent
60 pages.
Identifier
etd22161
Copyright statement
Copyright is held by the author(s).
Permissions
This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Supervisor or Senior Supervisor
Thesis advisor: Ruben, Peter C.
Language
English
Download file Size
etd22161.pdf 3.28 MB

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