SCN3A deficiency associated with increased seizure susceptibility

Tyra Lamar, Carlos Guillermo Vanoye, Jeffrey Calhoun, Jennifer C. Wong, Stacey B.B. Dutton, Benjamin S. Jorge, Milen Velinov, Andrew Escayg*, Jennifer A Kearney

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

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+/Hyp mice 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.

Original languageEnglish (US)
Pages (from-to)38-48
Number of pages11
JournalNeurobiology of Disease
Volume102
DOIs
StatePublished - Jun 1 2017

Fingerprint

Seizures
Partial Epilepsy
Mutation
Epilepsy
Flurothyl
Voltage-Gated Sodium Channels
Exome
Biotinylation
Induced Hyperthermia
Kainic Acid
Autonomic Nervous System
Locomotion
Genes
Sodium
Alleles
Cell Membrane
Learning
Brain
Proteins

Keywords

  • Focal epilepsy
  • Na1.3
  • SCN3A
  • Seizure susceptibility
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • Neurology

Cite this

Lamar, Tyra ; Vanoye, Carlos Guillermo ; Calhoun, Jeffrey ; Wong, Jennifer C. ; Dutton, Stacey B.B. ; Jorge, Benjamin S. ; Velinov, Milen ; Escayg, Andrew ; Kearney, Jennifer A. / SCN3A deficiency associated with increased seizure susceptibility. In: Neurobiology of Disease. 2017 ; Vol. 102. pp. 38-48.
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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+/Hyp mice 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.",
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Lamar, T, Vanoye, CG, Calhoun, J, Wong, JC, Dutton, SBB, Jorge, BS, Velinov, M, Escayg, A & Kearney, JA 2017, 'SCN3A deficiency associated with increased seizure susceptibility', Neurobiology of Disease, vol. 102, pp. 38-48. https://doi.org/10.1016/j.nbd.2017.02.006

SCN3A deficiency associated with increased seizure susceptibility. / Lamar, Tyra; Vanoye, Carlos Guillermo; Calhoun, Jeffrey; Wong, Jennifer C.; Dutton, Stacey B.B.; Jorge, Benjamin S.; Velinov, Milen; Escayg, Andrew; Kearney, Jennifer A.

In: Neurobiology of Disease, Vol. 102, 01.06.2017, p. 38-48.

Research output: Contribution to journalArticle

TY - JOUR

T1 - SCN3A deficiency associated with increased seizure susceptibility

AU - Lamar, Tyra

AU - Vanoye, Carlos Guillermo

AU - Calhoun, Jeffrey

AU - Wong, Jennifer C.

AU - Dutton, Stacey B.B.

AU - Jorge, Benjamin S.

AU - Velinov, Milen

AU - Escayg, Andrew

AU - Kearney, Jennifer A

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