Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus

• Published in: American journal of human genetics 2002-02, Vol.70 (2), p.530
• Main Authors: Harkin, Louise A, Bowser, David N, Dibbens, Leanne M, Singh, Rita, Phillips, Fiona, Wallace, Robyn H, Richards, Michaella C, Williams, David A, Mulley, John C, Berkovic, Samuel F, Scheffer, Ingrid E, Petrou, Steven
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Cell Line; Codon, Terminator - genetics; Electrophysiology; Endoplasmic Reticulum - metabolism; Epilepsies, Myoclonic - complications; Epilepsies, Myoclonic - genetics; Epilepsy, Generalized - complications; Epilepsy, Generalized - genetics; Female; gamma-Aminobutyric Acid - pharmacology; Humans; Male; Models, Molecular; Oocytes - drug effects; Oocytes - metabolism; Pedigree; Protein Conformation; Protein Subunits; Receptors, GABA-A - chemistry; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Seizures, Febrile - complications; Seizures, Febrile - genetics; Sequence Deletion - genetics; Xenopus laevis
• ISSN: 0002-9297
• DOI: 10.1086/338710

Recent findings from studies of two families have shown that mutations in the GABA(A)-receptor gamma2 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 gamma2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA(A)-receptor gamma2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant gamma2(Q351X) subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled gamma2(Q351X) protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA(A) receptors in epilepsy.