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.

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

“…Our data show that the mutation M1841T of Na v 1.1 Na ϩ channel, identified in a GEFSϩ family with a particularly large phenotypic spectrum ranging from mild FSϩ to SMEI (Annesi et al, 2003), causes a complete loss of function of Na v 1.1, similarly to other described GEFSϩ mutations (Lossin et al, 2003). This effect is analogous to that of many SMEI mutations that cause truncations and consequently complete loss of function of Nav1.1, the haploinsufficiency of which generates seizures probably by decreasing excitability of GABAergic neurons, as observed in Na v 1.1 knock-out mice (Yu et al, 2006).…”

“…Moreover, similarly to many SMEI mutations, some GEFSϩ mutations cause a complete loss of function (Lossin et al, 2003), complicating genotype-phenotype correlation and thus early diagnosis and genetic counseling (Ferraro et al, 2006).…”

“…For instance, the functional effects of some GEFSϩ mutations are similar to those of SMEI mutations, a much more severe epilepsy characterized also by cognitive impairment and high mortality rate (Dravet et al, 2005). In particular, some GEFSϩ missense mutations cause complete loss of function of the mutant channel, as the majority of SMEI mutations (Lossin et al, 2003). Moreover, GEFSϩ families show a large phenotypic variability that ranges from mild phenotypes to very severe ones (Scheffer and Berkovic, 1997).…”

Fibroblast growth factor homologous factors: Evolution, structure, and function

“…Domains I-IV are linked by three large intracellular loops, and domain IV is followed by a cytoplasmic C-terminal tail ranging from 200-300 amino acid residues. The S4 segment in each domain acts as a voltage sensor undergoing a voltage-dependent conformation change and mediating channel activation following depolarization (Lossin et al, 2003). The III-IV loop plays a critical role in voltage-dependent channel inactivation, thereby limiting channel opening to a 1-2 msec window following depolarization.…”

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

“…Since the description of the first SCN1A mutations in families with GEFSϩ in 2000, 10 additional mutations have been described, accounting for the disease in 50% of families studied (Escayg et al, 2000Abou-Khalil et al, 2001;Sugawara et al, 2001;Wallace et al, 2001;Annesi et al, 2003;Fujiwara et al, 2003;Lossin et al, 2003). Most of these are located within or adjacent to transmembrane segments or in the pore region of the channel.…”