Hereditary Defects in Human Sodium Channels

Project: Research project

Project Details


Voltage-gated sodium (NaV) channels are heteromultimeric integral membrane proteins that are responsible for the initial phase of the action potential in most excitable cells. A variety of inherited disorders affecting skeletal muscle contraction (hyperkalemic periodic paralysis, paramyotonia congenita, K+-aggravated myotonia), cardiac excitability (congenital long QT syndrome, idiopathic ventricular fibrillation, familial conduction system disease) and certain forms of epilepsy have been associated with mutations in human NaV channel genes. This proposal is a competing renewal of R01-NS32387 that for 17 years has funded our efforts to elucidate the molecular genetic, pathophysiologic and pharmacologic mechanisms of human sodium "channelopathies". We propose to continue our highly successful research program with a focus on epilepsies associated with mutant brain NaV channels. In Specific Aim 1, we will elucidate the functional consequences of novel epilepsy-associated SCN1A (encoding NaV1.1) mutations with a focus on two unstudied mechanistic aspects of mutant channel dysfunction. First, we will investigate the functional consequences of a subset of mutations within a region of the NaV1.1 C-terminus having conserved Ca2+/calmodulin regulatory elements to test the hypothesis that these alleles affect channel function by altering the response of the channel to internal Ca2+ signaling. Second, we will investigate whether alternative splicing influences the functional consequences of SCN1A mutations associated with divergent clinical phenotypes. In Specific Aim 2, we will elucidate the neurophysiological basis for straindependent epilepsy severity using two mechanistically distinct mouse models of epilepsy caused by mutant NaV channels: 1) transgenic mice expressing a gain-of-function Scn2a mutation (Q54 mice); and 2) heterozygous Scn1a knock out (Scn1a+/-) mice, a model of human Dravet syndrome. Both models exhibit strong strain-dependence of epilepsy severity and impaired survival. Strain-dependence of murine phenotypes mimics the variable penetrance and disease expression characteristic of human monogenic epilepsies including those caused by mutant NaV channels. Ongoing efforts to map genomic loci responsible for this phenomenon have identified a new candidate gene for seizure susceptibility using Q54 mice. By integrating existing and future genomic data on modifiers of epilepsy with information about the neurophysiological correlates of phenotype strain-dependence, we expect to generate important new insights into mechanisms responsible for the influence of genetic modifiers relevant
Effective start/end date3/1/144/30/17


  • National Institute of Neurological Disorders and Stroke (5R01NS032387-23)


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