Mutated GABAA receptor subunits in idiopathic generalized epilepsy

Excerpt

Although idiopathic generalized epilepsies (IGE) are generally complex genetic traits, there have been an increasing number of reports over the past ten years on rare forms of familial epilepsy where the mode of inheritance is clearly Mendelian. We and others reported on monogenic IGE associated with mutations in GABA_A receptor genes. GABA_A receptors are ligand-gated chloride channels that mediate fast inhibition in the adult CNS. Their molecular structure comprises of a heteropentameric protein complex assembled from 19 different subunits (α1–6, β1–3, γ1–3, δ, ɛ, π, θ, and ρ1–3). So far, epilepsy-causing mutations have been identified in the α1, γ2, β3 and δ subunits. In vitro functional studies revealed that the majority of these mutations result in a reduction of GABA-activated chloride currents. In many of these mutations, it has been shown that the reduction in the amplitude of GABA-evoked current was due to reduced surface expression of receptor protein. Taken together, these results suggest that loss of function mutations in GABA_A receptor genes is an important mechanism in the pathophysiology of familial IGE. Although additional mechanisms are involved in the pathogenesis of IGE, these results provide important insights in the pathogenesis of these ‘idiopathic’ epilepsies.