title: A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: common mechanism in Nav1.1 related epilepsies?
abstract: Mutations of voltage-gated Na(+) channels are the most common known cause of genetically determined epilepsy; Na(v)1.1 (SCN1A) is the most frequent target. They can cause both mild and severe forms, also in patients harboring the same mutation. We have recently characterized in a family with extreme phenotypes the first epileptogenic folding-defective Na(+) channel mutant (Na(v)1.1-M1841T), whose loss of function is attenuated by interactions with associated proteins and drugs. We hypothesized that in vivo variability of the interactions may modulate the functional effect and thus the phenotype (Rusconi et al., 2007). Here we characterize another Na(v)1.1 folding-defective mutant (Na(v)1.1-R1916G) that, however, has been identified in a GEFS+ family with relatively mild phenotypes. This novel mutant shows a number of specific characteristics, but, similarly to Na(v)1.1-M1841T, it can be rescued by interactions with associated proteins and drugs. Thus, loss of function caused by folding defects that can be attenuated by molecular interactions may be a common pathogenic mechanism for Na(v)1.1 epileptogenic mutants. Folding defects can be present also in families showing only mild phenotypes in which, however, severe phenotypes could emerge within a permissive genetic background.
authors.affiliation: Department of Neurophysiopathology, C.Besta Neurological Institute, 20133 Milano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.forename: Romina
authors.initials: R
authors.lastname: Combi
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cestèle
authors.forename: Daniele
authors.initials: D
authors.lastname: Grioni
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Leda
authors.initials: L
authors.lastname: Dalprà
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
mesh_terms: D002460:Cell Line; D018076:DNA, Complementary; D004827:Epilepsy / Q000209:etiology* / Q000235:genetics; D005192:Family Health; D006801:Humans; D050505:Mutant Proteins / Q000502:physiology; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017510:Protein Folding; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D050505:Mutant Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels