Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A.
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.
Lossin
Christoph
C
Neuroscience Graduate Program, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0275, USA.
Rhodes
Thomas H
TH
Desai
Reshma R
RR
Vanoye
Carlos G
CG
Wang
Dao
D
Carniciu
Sanda
S
Devinsky
Orrin
O
George
Alfred L
AL
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*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels