Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects

Abstract

The human sodium channel family includes seven neuronal channels that are essential for the initiation and propagation of action potentials in the CNS and PNS. In view of their critical role in neuronal firing and their strong sequence conservation during evolution, it is not surprising that mutations in the sodium channel genes are responsible for a growing spectrum of channelopathies. Nearly 700 mutations of the SCN1A gene have been identified in patients with Dravet's syndrome (severe myoclonic epilepsy of infancy), making this the most commonly mutated gene in human epilepsy. A small number of mutations have been found in SCN2A, SCN3A and SCN9A, and studies in the mouse suggest that SCN8A may also contribute to seizure disorders. Interactions between genetic variants of SCN2A and KCNQ2 in the mouse and variants of SCN1A and SCN9A in patients provide models of potential genetic modifier effects in the more common human polygenic epilepsies. New methods for generating induced pluripotent stem cells and neurons from patients will facilitate functional analysis of amino acid substitutions in channel proteins. Whole genome sequencing and exome sequencing in patients with epilepsy will soon make it possible to detect multiple variants and their interactions in the genomes of patients with seizure disorders.

Figure 2. Tissue specificity and number of reported epilepsy mutations in the 9 functional voltage-gated sodium channel genes

A, conserved domains of the sodium channel α-subunit protein. D, homologous domains; p, pore loops; L, inter-domain loops; +, positively charged transmembrane segments contributing to voltage sensing. B, major sites of expression of the sodium channel genes and numbers of mutations identified in patients with epilepsy.

Figure 1. Genomic arrangement of 10 paralogous human genes encoding α subunits of the voltage-gated sodium channels

Protein nomenclature is indicated below the gene symbol. Arrows represent the direction of transcription. Data from the UCSC genome browser at http://www.genome.ucsc.edu