Multiple molecular mechanisms for a single GABAA mutation in epilepsy

To understand the molecular basis and differential penetrance of febrile seizures and absence seizures in patients with the γ2(R43Q) GABA receptor mutation.

Spike-and-wave discharges and thermal seizure susceptibility were measured in heterozygous GABA γ2 knock-out and GABA γ2(R43Q) knock-in mice models crossed to different mouse strains.

By comparing the GABA γ2 knock-out with the GABA γ2(R43Q) knock-in mouse model we show that haploinsufficiency underlies the genesis of absence seizures but cannot account for the thermal seizure susceptibility. Additionally, while the expression of the absence seizure phenotype was very sensitive to mouse background genetics, the thermal seizure phenotype was not.

Our results show that a single gene mutation can cause distinct seizure phenotypes through independent molecular mechanisms. A lack of effect of genetic background on thermal seizure susceptibility is consistent with the higher penetrance of febrile seizures compared to absence seizures seen in family members with the mutation. These mouse studies help to provide a conceptual framework within which clinical heterogeneity seen in genetic epilepsy can be explained.