GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

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 GABA A receptor 8 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 Arg220Hls allele in GABRD which is present in the general population. Compared with wild-type receptors, α1β2Sδ GABA A receptors containing 8 Glu177Ala or Arg220Hls have decreased GABA A receptor current amplitudes. As GABA A receptors mediate neuronal Inhibition, the reduced receptor current associated with both variants is likely to be associated with Increased neuronal excitability. Since δ 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.