title: Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome.
abstract: Relatively few SCN1A mutations associated with genetic epilepsy with febrile seizures-plus (GEFS+) and Dravet syndrome (DS) have been functionally characterized. In contrast to GEFS+, many mutations detected in DS patients are predicted to have complete loss of function. However, functional consequences are not immediately apparent for DS missense mutations. Therefore, we performed a biophysical analysis of three SCN1A missense mutations (R865G, R946C and R946H) we detected in six patients with DS. Furthermore, we compared the functionality of the R865G DS mutation with that of a R859H mutation detected in a GEFS+ patient; the two mutations reside in the same voltage sensor domain of Na(v) 1.1. The four mutations were co-expressed with β1 and β2 subunits in tsA201 cells, and characterized using the whole-cell patch clamp technique. The two DS mutations, R946C and R946H, were nonfunctional. However, the novel voltage sensor mutants R859H (GEFS+) and R865G (DS) produced sodium current densities similar to those in wild-type channels. Both mutants had negative shifts in the voltage dependence of activation, slower recovery from inactivation, and increased persistent current. Only the GEFS+ mutant exhibited a loss of function in voltage-dependent channel availability. Our results suggest that the R859H mutation causes GEFS+ by a mixture of biophysical defects in Na(v) 1.1 gating. Interestingly, while loss of Na(v) 1.1 function is common in DS, the R865G mutation may cause DS by overall gain-of-function defects.
authors.affiliation: Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Volkers
authors.forename: Kristopher M
authors.initials: KM
authors.lastname: Kahlig
authors.forename: Nienke E
authors.initials: NE
authors.lastname: Verbeek
authors.forename: Joost H G
authors.initials: JH
authors.lastname: Das
authors.forename: Marjan J A
authors.initials: MJ
authors.lastname: van Kempen
authors.forename: Hans
authors.initials: H
authors.lastname: Stroink
authors.forename: Paul
authors.initials: P
authors.lastname: Augustijn
authors.forename: Onno
authors.initials: O
authors.lastname: van Nieuwenhuizen
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Martin B
authors.initials: MB
authors.lastname: Rook
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007223:Infant; D015640:Ion Channel Gating / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D003294:Seizures, Febrile / Q000235:genetics* / Q000503:physiopathology*; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013577:Syndrome
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels