SCN3A deficiency associated with increased seizure susceptibility

• Type of Material: Article
• Authors: Tyra Lamar, Emory University; Carlos G. Vanoye, Northwestern University; Jeffrey Calhoun, Northwestern University; Jennifer Wong, Emory University; Stacey B.B. Dutton, Emory University; Benjamin S. Jorge, Vanderbilt University; Milen Velinov, Albert Einstein College of Medicine; Andrew Escayg, Emory University; Jennifer A. Kearney, Northwestern University
• Language: English
• Date: 2017-06-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2017.02.006
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 102
• Start Page: 38
• End Page: 48
• Grant/Funding Information: Imaging was performed with a CRI Nuance spectral camera purchased with support from the Avon Foundation to Charles Clevenger.; This work was supported by NIH grants to J.A.K. (NS053792) and A.E. (NS072221 and NS090319).; Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
• Keywords: INTELLECTUAL DISABILITY; SUBUNIT MESSENGER-RNAS; DE-NOVO-SCN8A MUTATION; Seizure susceptibility; MISSENSE MUTATION; SODIUM-CHANNEL EXPRESSION; Life Sciences & Biomedicine; SEVERE MYOCLONIC EPILEPSY; DRAVET SYNDROME; Voltage-gated sodium channel; SCN3A; MOUSE MODEL; Science & Technology; Neurosciences; CENTRAL-NERVOUS-SYSTEM; Focal epilepsy; GENETIC EPILEPSY; Neurosciences & Neurology; Na(v)1.3
• Research Categories: Health Sciences, Pharmacology; Biology, Genetics; Biology, Neuroscience

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 (6 Hz) 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.