Identification of Epilepsy Genes in Human and Mouse

Abstract

The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

“…Mutations in four genes have been associated with GEFSϩ, the sodium channel ␣ subunits SCN1A and SCN2A, the sodium channel ␤1 subunit SCN1B, and the GABA A receptor ␥2 subunit GABRG2 (for review, see Meisler et al, 2001).…”

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

“…18 Missense mutations in SCN1A and SCN2A have been identified in the inherited seizure disorder Generalized Epilepsy with Febrile Seizures Plus (GEFS+2, MIM 604236, 604233). 19 De novo null mutations in SCN1A result in severe myoclonic epilepsy of infancy, a syndrome that includes mental retardation. 20 Mice expressing a mutated SCN2A channel with persistent current exhibit seizures and repetitive behaviors.…”

Contactin Associates with Sodium Channel Nav1.3 in Native Tissues and Increases Channel Density at the Cell Surface

“…Mutations of pore-forming ␣-subunits underlie a number of human and animal disorders (Goldin, 2001;Keating and Sanguinetti, 2001;Meisler et al, 2001), and dysregulated sodium channel expression may contribute to neuropathic pain .…”