Elsevier

Neurobiology of Disease

Volume 69, September 2014, Pages 117-123
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2014.05.017Get rights and content
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Highlights

  • Genetic investigation of a child with neonatal myoclonic jerks and seizures

  • Continuing intractable epilepsy and developmental delay at 3 years of age

  • Exome sequencing identified a de novo mutation in sodium channel SCN8A (Nav1.6).

  • Thr767Ile causes 10 mV depolarizing shift in voltage dependence of activation.

  • This 2nd SCN8A epilepsy mutation enhances channel activity differently from the 1st.

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 10 mV 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.

Keywords

Epilepsy
Sodium channel
De novo mutation
Epileptic encephalopathy

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