A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy

Mark Estacion, Janelle E. O'Brien, Allison Conravey, Michael F Hammer, Stephen G. Waxman, Sulayman D. Dib-Hajj, Miriam H. Meisler

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Rare de novo mutations of sodium channels are thought to be an important cause of sporadic epilepsy. The well established role of de novo mutations of sodium channel SCN1A in Dravet Syndrome supports this view, but the etiology of many cases of epileptic encephalopathy remains unknown. We sought to identify the genetic cause in a patient with early onset epileptic encephalopathy by whole exome sequencing of genomic DNA. The heterozygous mutation c. 2003C>T in SCN8A, the gene encoding sodium channel Nav1.6, was detected in the patient but was not present in either parent. The resulting missense substitution, p.Thr767Ile, alters an evolutionarily conserved residue in the first transmembrane segment of channel domain II. The electrophysiological effects of this mutation were assessed in neuronal cells transfected with mutant or wildtype cDNA. The mutation causes enhanced channel activation, with a 10mV depolarizing shift in voltage dependence of activation as well as increased ramp current. In addition, pyramidal hippocampal neurons expressing the mutant channel exhibit increased spontaneous firing with PDS-like complexes as well as increased frequency of evoked action potentials. The identification of this new gain-of-function mutation of Nav1.6 supports the inclusion of SCN8A as a causative gene in infantile epilepsy, demonstrates a novel mechanism for hyperactivity of Nav1.6, and further expands the role of de novo mutations in severe epilepsy.

Original languageEnglish (US)
Pages (from-to)117-123
Number of pages7
JournalNeurobiology of Disease
Volume69
DOIs
StatePublished - 2014

Fingerprint

Brain Diseases
Mutation
Sodium Channels
Epilepsy
Myoclonic Epilepsy
Exome
Architectural Accessibility
Pyramidal Cells
DNA Sequence Analysis
Evoked Potentials
Genes
Action Potentials
Complementary DNA

Keywords

  • De novo mutation
  • Epilepsy
  • Epileptic encephalopathy
  • Sodium channel

ASJC Scopus subject areas

  • Neurology
  • Medicine(all)

Cite this

A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. / Estacion, Mark; O'Brien, Janelle E.; Conravey, Allison; Hammer, Michael F; Waxman, Stephen G.; Dib-Hajj, Sulayman D.; Meisler, Miriam H.

In: Neurobiology of Disease, Vol. 69, 2014, p. 117-123.

Research output: Contribution to journalArticle

Estacion, Mark ; O'Brien, Janelle E. ; Conravey, Allison ; Hammer, Michael F ; Waxman, Stephen G. ; Dib-Hajj, Sulayman D. ; Meisler, Miriam H. / A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. In: Neurobiology of Disease. 2014 ; Vol. 69. pp. 117-123.
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