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First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene

Nature Genetics volume 28, pages 46–48 (2001)Cite this article

Abstract

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, respectively1,2,3,4,5,6. Disruption of GABAergic neurotransmission mediated by γ-aminobutyric acid (GABA) has been implicated in epilepsy for many decades7. We now report a K289M mutation in the GABAA receptor γ2-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 genes1,2. 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 GABAA receptor is directly involved in human idiopathic epilepsy.

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Figure 1: Pedigree and mutation segregation in the family with GEFS+ (+, wild type; m, mutant).
Figure 2: Structure and evolutionary conservation of the lysine residue in GABRG2.
Figure 3: Effect of the γ2K289M mutation on GABA-evoked currents (IGABA) in X. laevis oocytes.

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Acknowledgements

We thank M. Ruberg for critically reading the manuscript. This work was funded by the Association pour le Développement de la Recherche sur les Maladies Génétiques Neurologiques et Psychiatriques, the Association Française contre les Myopathies, the Association RETINA France, Généthon and the Association pour la Recherche sur la Génétique des Epilepsies sponsored by Sanofi-Synthelabo.

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Authors and Affiliations

  1. INSERM U289, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France

    Stéphanie Baulac, Gilles Huberfeld, Alexandre Beranger, Alexis Brice & Eric LeGuern

  2. Centre d'Epileptologie, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France

    Isabelle Gourfinkel-An & Michel Baulac

  3. Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France

    Alexis Brice & Eric LeGuern

  4. Généthon, Evry, France

    Isabelle Gourfinkel-An & Jean-François Prud'homme

  5. NRSN, Institut Pasteur, Paris, France

    Georgia Mitropoulou & Roberto Bruzzone

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  1. Stéphanie Baulac
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Correspondence to Eric LeGuern.

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Baulac, S., Huberfeld, G., Gourfinkel-An, I. et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nat Genet 28, 46–48 (2001). https://doi.org/10.1038/ng0501-46

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