Chapter 10 - Mutations of Sodium Channel SCN8A (Nav1.6) in Neurological Disease

Abstract

The voltage-gated sodium channel Nav1.6, encoded by the SCN8A gene, is one of the most abundant sodium channels in human brain. In the axon initial segment of neurons, Nav1.6 regulates the initiation of action potentials, and at nodes of Ranvier it contributes to nerve conduction velocity. Complete loss of Scn8a in the mouse results in paralysis due to failure of the neuromuscular junction, while partial loss-of-function mutations result in gait disorders, ataxia, and dystonia. The role of SCN8A in epilepsy has been recently revealed by large-scale exome sequencing. De novo missense mutations of SCN8A account for approximately 1% of cases of early infantile epileptic encephalopathy, designated EIEE13 (OMIM #614558). Heterozygous null mutations of SCN8A mutations can also result in isolated cognitive impairment. In cardiac myocytes, Nav1.6 is localized to the transverse tubules where it functions in excitation–contraction coupling. Cardiac arrhythmias in patients with EIEE13 may contribute to sudden death (sudden unexpected death in epilepsy). The biophysical and pathogenic effects of missense mutations of SCN8A are being studied in transfected cells and knock-in mouse models. The emerging information suggests that mutations causing hyperactivity of Nav1.6 result in epileptic encephalopathy, while loss-of-function mutations contribute to cognitive impairment and anxiety, and perhaps to psychiatric disease.