A novel de novo mutation of SCN8A (Na(v)1.6) with enhanced channel activation in a child with epileptic encephalopathy

作者：Estacion Mark; O'Brien Janelle E; Conravey Allison; Hammer Michael F; Waxman Stephen G; Dib Hajj Sulayman D^*; Meisler Miriam H

来源：Neurobiology of Disease, 2014, 69: 117-123.

DOI：10.1016/j.nbd.2014.05.017

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

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 Na(v)1.6, 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 Na(v)1.6 supports the inclusion of SCN8A as a causative gene in infantile epilepsy, demonstrates a novel mechanism for hyperactivity of Na(v)1.6, and further expands the role of de novo mutations in severe epilepsy.

• 出版日期2014-9