title: A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel.
abstract: Seizure susceptibility is high in human infants compared to adults, presumably because of developmentally regulated changes in neural excitability. Benign familial neonatal-infantile seizures (BFNIS), characterized by both early onset and remission, are caused by mutations in the gene encoding a human sodium channel (NaV1.2). We analyzed neonatal and adult splice forms of NaV1.2 with a BFNIS mutation (L1563V) in human embryonic kidney cells. Computer modeling revealed that neonatal channels are less excitable than adult channels. Introduction of the mutation increased excitability in the neonatal channels to a level similar to adult channels. By contrast, the mutation did not affect the adult channel variant. This "adult-like" increased excitability is likely to be the mechanism underlying BFNIS in infants with this mutation. More generally, developmentally regulated NaV1.2 splicing may be one mechanism that counters the normally high excitability of neonatal neurons and helps to reduce seizure susceptibility in normal human infants.
authors.affiliation: Howard Florey Institute, The University of Melbourne, Parkville, Victoria, 3010, Melbourne, Australia.
authors.forename: Ruwei
authors.initials: R
authors.lastname: Xu
authors.forename: Evan A
authors.initials: EA
authors.lastname: Thomas
authors.forename: Misty
authors.initials: M
authors.lastname: Jenkins
authors.forename: Elena V
authors.initials: EV
authors.lastname: Gazina
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiu
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
mesh_terms: D000328:Adult; D002461:Cell Line, Transformed; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D004827:Epilepsy / Q000235:genetics*; D006801:Humans; D007223:Infant; D008564:Membrane Potentials / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; D015222:Sodium Channels