Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability

Abstract

The sodium channel Nav1.6, encoded by the gene SCN8A, is one of the major voltage-gated channels in human brain. The sequences of sodium channels have been highly conserved during evolution, and minor changes in biophysical properties can have a major impact in vivo. Insight into the role of Nav1.6 has come from analysis of spontaneous and induced mutations of mouse Scn8a during the past 18 years. Only within the past year has the role of SCN8A in human disease become apparent from whole exome and genome sequences of patients with sporadic disease. Unique features of Nav1.6 include its contribution to persistent current, resurgent current, repetitive neuronal firing, and subcellular localization at the axon initial segment (AIS) and nodes of Ranvier. Loss of Nav1.6 activity results in reduced neuronal excitability, while gain-of-function mutations can increase neuronal excitability. Mouse Scn8a (med) mutants exhibit movement disorders including ataxia, tremor and dystonia. Thus far, more than ten human de novo mutations have been identified in patients with two types of disorders, epileptic encephalopathy and intellectual disability. We review these human mutations as well as the unique features of Nav1.6 that contribute to its role in determining neuronal excitability in vivo. A supplemental figure illustrating the positions of amino acid residues within the four domains and 24 transmembrane segments of Nav1.6 is provided to facilitate the location of novel mutations within the channel protein.

Keywords: Nav1.6; SCN8A; epilepsy; exomes; genetics; intellectual disability; neurogenetics; voltage-gated sodium channels.

Figure 1

Increased persistent current in SCN8A-p.Asn1768Asp mutant channel. Wildtype and mutant cDNAs were transiently transfected into the neuronal cell line ND7/23. At 100 ms after induction of an action potential, cells expressing the mutant cDNA had 20% persistent current compared with 1% in the wildtype. Cells were held at −120 mV, and a family of step depolarizations (−80 to +60 mV in 5 mV increments) were applied every 5 s. Insets show persistent inward currents (normalized by maximal transient peak currents) from WT and p.Asn1768Asp channels at the end of a 100 ms step depolarization to −80 mV (black, control) and +20 mV (red). [reprinted from Veeramah et al. (2012), with permission].

Figure 2

Mutations of human SCN8A. The positions of twelve recently identified mutations of SCN8A are indicated on the backbone of the channel structure. The four homologous domains are labeled with the pore domains in green, the voltage-sensing transmembrane segments (S4) in blue, and the inactivation gate in red. Filled circles, mutations identified in patients with epilepsy. Open circles, mutations identified in patients with cognitive deficits. Unpublished mutations are shown in their approximate positions.

Figure 3

Mutations of mouse Scn8a. Fourteen allelic mutations are shown on the channel backbone as described in Figure 2. Amino acids are numbered according to Genbank AF049617. Filled circles, null alleles; open circles, hypomorphic alleles.

Figure 4

Locations of protein interactions with Na_v1.6. Filled circles represent binding sites that have been localized to specific residues of Na_v1.6: Map1b (77–80), p38 (553), ankyrin (1089–1122), calmodulin (1902–1912), and Nedd4 (551–554 and 1943–1945). Open symbols, binding sites that have not been mapped to specific residues.