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Recent findings from studies of two families have shown that mutations in the GABA(A)-receptor gamma2 subunit are associated with generalized epilepsies and febrile seizures. Here we describe a family that has generalized epilepsy with febrile seizures plus (GEFS(+)), including an individual with severe myoclonic epilepsy of infancy, in whom a third GABA(A)-receptor gamma2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA(A)-receptor gamma2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant gamma2(Q351X) subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled gamma2(Q351X) protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA(A) receptors in epilepsy.

Rare GABAA receptor γ2 and α1 subunit mutations of pathogenic effect have been described segregating in families with “monogenic” epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABAA receptor subunit genes from the one patient cohort. The cohort consists of GEFS+, FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABAA receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations. Refereed/Peer-reviewed

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.

Mutations in the voltage gated potassium channels KCNQ2 (OMIM 602235) and KCNQ3 (OMIM 602232) are associated with an autosomal dominant idiopathic epilepsy syndrome of newborns, benign familial neonatal seizures (BFNS) (OMIM 121200). BFNS is characterised by unprovoked partial seizures typically beginning when the infant is around three days old. BFNS associated genes were mapped to human chromosomes 20q13.31 and 8q24,2 which led to the identification by positional cloning of KCNQ2 as the chromosome 20 gene.3,4 KCNQ3 was subsequently identified as the 8q24 BFNS gene, based on genomic location and homology with KCNQ2.5 The potassium channels of the KCNQ gene family consist of four subunits, each with a 6 transmembrane topological organisation. KCNQ subunits, comprising KCNQ1–5, have an intracellular amino terminus, a single pore loop (P-loop) that forms the selectivity filter of the channel,6 a positively charged, voltage sensing fourth transmembrane domain (S4), and a large intracellular carboxy terminus (C-terminus). All five known KCNQ proteins can form homomeric channels, but the association of specific subunits to form heteromeric channels is restricted to certain combinations.6–10 KCNQ2 and KCNQ3 are mostly expressed in the central nervous system,3–5 where they form a heteromultimeric channel that mediates the neuronal muscarinic regulated current (M-current), also known as an M-channel (or M-type K+ channel). The M-current is a slowly activating, non-inactivating potassium conductance known to regulate neuronal excitability by determining the firing properties of neurones and their responsiveness to synaptic input.11 Because it is active at voltages near the threshold for action potential initiation, the M-current has a major impact on neuronal excitability. Since the KCNQ2/KCNQ3 ion channel plays a pivotal role in the regulation of neuronal excitability, it is not surprising that several mutations in the gene have been associated with epilepsy. The first …

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.