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The Journal of Neuroscience, December 10, 2003, 23(36):11289-11295
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Cellular/Molecular
Epilepsy-Associated Dysfunction in the Voltage-Gated Neuronal Sodium Channel SCN1A
Christoph Lossin,1 Thomas H. Rhodes,2 Reshma R. Desai,2 Carlos G. Vanoye,2 Dao Wang,3 Sanda Carniciu,4 Orrin Devinsky,4 andAlfred L. George, Jr2,3 1Neuroscience Graduate Program, 2Division of Genetic Medicine, Department of Medicine, and 3Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-0275, and 4Department of Neurology, New York University, New York, New York 10016
Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel
1 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.
Key words: epilepsy; sodium channel; GEFS+; SMEI; SCN1A; electrophysiology
Received Sep 2, 2003; revised October 9, 2003; accepted October 9, 2003.
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