Truncation of the GABA A-Receptor γ2 Subunit in a Family with Generalized Epilepsy with Febrile Seizures Plus

Recent findings from studies of two families have shown that mutations in the GABA A -receptor γ2 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 γ2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA A -receptor γ2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant γ2 Q351X subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled γ2 Q351X protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA A receptors in epilepsy.