title: Sodium channel SCN1A and epilepsy: mutations and mechanisms.
abstract: Mutations in a number of genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes in humans, including genetic (generalized) epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS, severe myoclonic epilepsy of infancy). Most of these mutations are in the SCN1A gene, and all are dominantly inherited. Most of the mutations that cause DS result in loss of function, whereas all of the known mutations that cause GEFS+ are missense, presumably altering channel activity. Family members with the same GEFS+ mutation often display a wide range of seizure types and severities, and at least part of this variability likely results from variation in other genes. Many different biophysical effects of SCN1A-GEFS+ mutations have been observed in heterologous expression systems, consistent with both gain and loss of channel activity. However, results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons. Decreased activity of the inhibitory circuitry is thus likely to be a major factor contributing to seizure generation in patients with GEFS+ and DS, and may be a general consequence of SCN1A mutations.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA. aescayg@emory.edu
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
authors.forename: Alan L
authors.initials: AL
authors.lastname: Goldin
mesh_terms: D000818:Animals; D053447:Channelopathies / Q000235:genetics; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000235:genetics*; D006801:Humans; D051379:Mice; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats; D003294:Seizures, Febrile / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; C568250:Scn1a protein, rat; D015222:Sodium Channels