title: Molecular basis of an inherited epilepsy.
abstract: Epilepsy is a common neurological condition that reflects neuronal hyperexcitability arising from largely unknown cellular and molecular mechanisms. In generalized epilepsy with febrile seizures plus, an autosomal dominant epilepsy syndrome, mutations in three genes coding for voltage-gated sodium channel alpha or beta1 subunits (SCN1A, SCN2A, SCN1B) and one GABA receptor subunit gene (GABRG2) have been identified. Here, we characterize the functional effects of three mutations in the human neuronal sodium channel alpha subunit SCN1A by heterologous expression with its known accessory subunits, beta1 and beta2, in cultured mammalian cells. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality will likely enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for this inherited human epilepsy.
authors.affiliation: Division of Genetic Medicine, Center for Molecualr Neurosciences, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lossin
authors.forename: Dao W
authors.initials: DW
authors.lastname: Wang
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rhodes
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D002478:Cells, Cultured; D003001:Cloning, Molecular; D004829:Epilepsy, Generalized / Q000235:genetics*; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels