title: Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome.
abstract: Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss-of-function mutations in SCN1A, the gene encoding brain sodium channel Nav 1.1. DS is associated with increased frequency of sudden unexpected death in humans and in a mouse genetic model of this disease. Here we correlate the time course of declining expression of the murine embryonic sodium channel Nav 1.3 and the rise in expression of the adult sodium channel Nav 1.1 with susceptibility to epileptic seizures and increased incidence of sudden death in DS mice. Parallel studies with unaffected human brain tissue demonstrate similar decline in Nav 1.3 and increase in Nav 1.1 with age. In light of these results, we introduce the hypothesis that the natural loss Nav 1.3 channel expression in brain development, coupled with the failure of increase in functional Nav 1.1 channels in DS, defines a tipping point that leads to disinhibition of neural circuits, intractable seizures, co-morbidities, and premature death in this disease.
authors: Department of Pharmacology; University of Washington; Seattle, WA USA.
authors: Christine S
authors: CS
authors: Cheah
authors: Department of Pharmacology; University of Washington; Seattle, WA USA.
authors: Ruth E
authors: RE
authors: Westenbroek
authors: Center for Integrative Brain Research; Seattle Children's Research Institute; Seattle, WA USA.
authors: William H
authors: WH
authors: Roden
authors: Department of Pharmacology; University of Washington; Seattle, WA USA.
authors: Franck
authors: F
authors: Kalume
authors: Department of Neurology; University of Washington; Seattle, WA USA.
authors: John C
authors: JC
authors: Oakley
authors: Center for Integrative Brain Research; Seattle Children's Research Institute; Seattle, WA USA; Department of Neurology; University of Washington; Seattle, WA USA.
authors: Laura A
authors: LA
authors: Jansen
authors: Department of Pharmacology; University of Washington; Seattle, WA USA.
authors: William A
authors: WA
authors: Catterall
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D003645:Death, Sudden; D004831:Epilepsies, Myoclonic / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000378:metabolism; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D013997:Time Factors
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels
keywords: Dravet syndrome; epilepsy; ion channel; premature death; seizure; sodium channel
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