title: Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A.
abstract: Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel alpha1 subunit (NaV1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor I1656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS+ mutations (A1685V and V1353L) and L986F, an SMEI-associated allele, exhibited complete loss of function. In conclusion, our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles.
authors.affiliation: Neuroscience Graduate Program, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lossin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rhodes
authors.forename: Reshma R
authors.initials: RR
authors.lastname: Desai
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Dao
authors.initials: D
authors.lastname: Wang
authors.forename: Sanda
authors.initials: S
authors.lastname: Carniciu
authors.forename: Orrin
authors.initials: O
authors.lastname: Devinsky
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D004553:Electric Conductivity; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000503:physiopathology; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D003294:Seizures, Febrile / Q000235:genetics / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels