Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy

The gamma-aminobutyric acid receptor type A (GABA(A) receptor) is a ligand-gated chloride channel that mediates major inhibitory functions in the central nervous system. GABA(A) receptors function mainly as pentamers containing alpha, beta, and either gamma or delta subunits. A number of antiepileptic drugs have agonistic effects on GABA(A) receptors. Hence, dysfunctions of GABA(A) receptors have been postulated to play important roles in the etiology of epilepsy. In fact, mutations or genetic variations of the genes encoding the alpha 1, alpha 6, beta 2, beta 3, gamma 2, or delta subunits (GABRA1, GABRA6, GABRB2, GABRB3, GABRG2, and GABRD, respectively) have been associated with human epilepsy, both with and without febrile seizures. Epilepsy resulting from mutations is commonly one of following, genetic (idiopathic) generalized epilepsy (e.g., juvenile myoclonic epilepsy), childhood absence epilepsy, genetic epilepsy with febrile seizures, or Dravet syndrome. Recently, mutations of GABRA1, GABRB2, and GABRB3 were associated with infantile spasms and Lennox-Gastaut syndrome. These mutations compromise hyperpolarization through GABA(A) receptors, which is believed to cause seizures. Interestingly, most of the insufficiencies are not caused by receptor gating abnormalities, but by complex mechanisms, including endoplasmic reticulum (ER)-associated degradation, nonsense-mediated mRNA decay, intracellular trafficking defects, and ER stress. Thus, GABA(A) receptor subunit mutations are now thought to participate in the pathomechanisms of epilepsy, and an improved understanding of these mutations should facilitate our understanding of epilepsy and the development of new therapies.