Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy

Abstract

Mutations of the voltage-gated sodium channel SCN8A have been identified in approximately 1% of nearly 1,500 children with early-infantile epileptic encephalopathies (EIEE) who have been tested by DNA sequencing. EIEE caused by mutation of SCN8A is designated EIEE13 (OMIM #614558). Affected children have seizure onset before 18 months of age as well as developmental and cognitive disabilities, movement disorders, and a high incidence of sudden death (SUDEP). EIEE13 is caused by de novo missense mutations of evolutionarily conserved residues in the Nav1.6 channel protein. One-third of the mutations are recurrent, and many occur at CpG dinucleotides. In this review, we discuss the effect of pathogenic mutations on the structure of the channel protein, the rate of recurrent mutation, and changes in channel function underlying this devastating disorder.

Keywords: CpG; Dravet syndrome; SUDEP; epilepsy; mutation; seizures; sodium channel.

Figure 1

Positions of missense mutations of SCN8A in epileptic encephalopathy. The four homologous domains of Na_v1.6 (DI to DIV) each contain six transmembrane segments (S1 to S6). The large inter-domain cytoplasmic loops 1 and 2 are evolutionarily less well-conserved than the transmembrane and linker domains. Loop 3 functions as the inactivation gate and is very highly conserved. Closed symbols, EIEE13 mutations in a single patient; open symbols, recurrent mutations.

Figure 2

Mechanism for recurrent mutation of SCN8A at CpG dinucleotides. Arginine 1617 is encoded by a CGA codon, and arginine 1872 is encoded by a CGG codon. Both contain CpG dinucleotides on coding and non-coding strands (small arrows). Cytosine methylation followed by deamination on either strand leads to mutation: at arginine 1617, replacement by the premature termination codon (TGA, Ter) or glutamine (Gln); at arginine 1872, replacement by tryptophan (Trp) or glutamine (Gln). The premature termination mutation p.Arg1617Ter has not been seen in EIEE13 patients, and would probably not cause seizures (see text).

Figure 3

Differential distribution of pathogenic and non-pathogenic variants in the protein domains of SCN8A. Mutations of patients with EIEE13 are compared with variation in the ExAC database (exac.broadinstitute.org, accessed 04/2015), which excludes severe pediatric disease. Each amino acid substitution was counted once. Data were available for 43 mutations in EIEE13 patients and 228 variants from the ExAC database. Filled bars, EIEE13 patients; open bars, ExAC controls; Inact. gate, inactivation gate.