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.
Highlights
Early-onset epileptic encephalopathy is a heterogenous disorder characterized by seizures, developmental delay and progressive loss of neurological function
We identified and functionally validated a gain-of-function mutation in SCN8A in a patient with epileptic encephalopathy and SUDEP (Veeramah et al, 2012)
We describe the distinct functional consequence of a second de novo mutation of SCN8A identified in a patient with a more severe epileptic encephalopathy
Summary
Early-onset epileptic encephalopathy is a heterogenous disorder characterized by seizures, developmental delay and progressive loss of neurological function. We identified and functionally validated a gain-of-function mutation in SCN8A in a patient with epileptic encephalopathy and SUDEP (Veeramah et al, 2012). Large-scale exome sequencing projects have identified eleven de novo mutations of SCN8A in singleton patients with epilepsy and/or intellectual disability (Rauch et al, 2012; Carvill et al, 2013; Epi4K Consortium, 2013; reviewed in O’Brien and Meisler, 2013). Another de novo mutation of SCN8A was recently identified in a child with epileptic encephalopathy and congenital anomalies (Vaher et al, 2013). Since genetic evidence of linkage is not possible for de novo mutations, functional studies and analysis of evolutionary conservation and population frequency can contribute to assessing the pathogenicity of these mutations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
