title: SCN3A deficiency associated with increased seizure susceptibility.
abstract: Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hypmice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, USA.
authors.forename: Tyra
authors.initials: T
authors.lastname: Lamar
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Calhoun
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Wong
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, USA.
authors.forename: Stacey B B
authors.initials: SBB
authors.lastname: Dutton
authors.affiliation: Neuroscience Program, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Jorge
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Milen
authors.initials: M
authors.lastname: Velinov
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, USA. Electronic address: aescayg@emory.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: jennifer.kearney@northwestern.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004828:Epilepsies, Partial / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012640:Seizures / Q000235:genetics* / Q000378:metabolism*; D015222:Sodium Channels / Q000172:deficiency* / Q000235:genetics*
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C424715:SCN3A protein, human; C515216:Scn3a protein, mouse; D015222:Sodium Channels
keywords: Focal epilepsy; Na(v)1.3; SCN3A; Seizure susceptibility; Voltage-gated sodium channel