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Author Notes:

Corresponding Authors Andrew Escayg, Ph.D., Department of Human Genetics, Whitehead Biomedical Research Building, 615 Michael Street, Suite 301, Emory University, Atlanta, Georgia, USA 30322, Tel: 404-712-8328, aescayg@emory.edu. Jennifer A. Kearney, Ph.D., Department of Pharmacology, Searle 8-510, 320 East Superior St., Northwestern University, Chicago, IL 60611, Tel: 312-503-4894, jennifer.kearney@northwestern.edu

The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

A full list of contributing groups can be found at http://exac.broadinstitute.org/about.

The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison.

We thank the patient and her family for their cooperation.

We also thank the Emory Rodent Behavioral core for performing the locomotor activity task.

Subjects:

Research Funding:

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.

Imaging was performed with a CRI Nuance spectral camera purchased with support from the Avon Foundation to Charles Clevenger.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • SCN3A
  • Na(v)1.3
  • Focal epilepsy
  • Voltage-gated sodium channel
  • Seizure susceptibility
  • SEVERE MYOCLONIC EPILEPSY
  • SODIUM-CHANNEL EXPRESSION
  • SUBUNIT MESSENGER-RNAS
  • CENTRAL-NERVOUS-SYSTEM
  • DRAVET SYNDROME
  • MOUSE MODEL
  • INTELLECTUAL DISABILITY
  • DE-NOVO-SCN8A MUTATION
  • MISSENSE MUTATION
  • GENETIC EPILEPSY

SCN3A deficiency associated with increased seizure susceptibility

Tools:

Journal Title:

Neurobiology of Disease

Volume:

Volume 102

Publisher:

, Pages 38-48

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 Elsevier Inc.

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