title: Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 Na+ channel mutant.
abstract: Familial epilepsies are often caused by mutations of voltage-gated Na+ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na(v)1.1 (SCN1A) Na+ channel alpha subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature <30 degrees C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na+ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.
authors.affiliation: Department of Neurophysiopathology, Besta Neurological Institute, 20133 Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.forename: Paolo
authors.initials: P
authors.lastname: Scalmani
authors.forename: Rita Restano
authors.initials: RR
authors.lastname: Cassulini
authors.forename: Giulia
authors.initials: G
authors.lastname: Giunti
authors.forename: Antonio
authors.initials: A
authors.lastname: Gambardella
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Enzo
authors.initials: E
authors.lastname: Wanke
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C568242:SCN1A protein, human; D015222:Sodium Channels