First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene

Nat Genet. 2001 May;28(1):46-8. doi: 10.1038/ng0501-46.


Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Chromosome Segregation
  • Conserved Sequence
  • Electric Conductivity
  • Epilepsy / genetics*
  • Epilepsy, Benign Neonatal / genetics
  • Epilepsy, Frontal Lobe / genetics
  • Epilepsy, Generalized / genetics
  • Female
  • Humans
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Protein Subunits
  • Receptors, GABA-A / genetics*
  • Seizures, Febrile / genetics
  • Sequence Homology, Amino Acid


  • Protein Subunits
  • Receptors, GABA-A

Associated data

  • GENBANK/AF165124