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

Am J Hum Genet. 2002 Feb;70(2):530-6. doi: 10.1086/338710. Epub 2001 Dec 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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
  • gamma-Aminobutyric Acid / pharmacology


  • Codon, Terminator
  • Protein Subunits
  • Receptors, GABA-A
  • gamma-Aminobutyric Acid