First Genetic Evidence of GABAA Receptor Dysfunction in Epilepsy: A Mutation in the [gamma] 2 Subunit Gene.
Abstract number :
E.04
Submission category :
Year :
2001
Submission ID :
1196
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
S. Baulac, Inserm U289, Hopital Pitie-Salpetriere, Paris, France; I. An-Gourfinkel, Center of Epilepsy, Hopital Pitie-Salpetriere, Paris, France; G. Huberfeld, Center of Epilepsy, Hopital Pitie-Salpetriere, Paris, France; M. Baulac, Center of Epilepsy, Ho
RATIONALE: We have studied a French family with 17 affected members with a phenotype closely related to Generalized Epilepsy with Febrile Seizures Plus (GEFS+), an autosomal dominant disorder associating febrile and generalized afebrile seizures and so far caused by mutations in sodium channel genes.
METHODS: Clinical and paraclinical investigations were performed on affected individuals. After excluding the loci previously implicated in GEFS+ and febrile seizures, we performed a genome-wide scan and screened candidate gene localized in the genetic interval.
RESULTS: Among the 17 affected members, 14 were included in the genetic analyses: 13 had histories of febrile seizures and 7 developed epilepsy (generalized tonic-clonic seizures), which was compatible with the GEFS+ context.
We have identified a K289M mutation in the GABAA receptor [gamma]2 subunit gene (GABRG2) that segregated in this family. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3.
Genetic evidence of the implication of this mutation was confirmed by functional analysis in Xenopus oocytes. The K289M mutation resulted in a dramatic decrease in the amplitude of GABA-activated currents compared to wild-type receptor. However, the current in the mutant channel was still potentiated by diazepam, demonstrating that the mutation doesn[ssquote]t affect the benzodiazepine site. Additional functional analysis will be presented concerning different drugs responses.
CONCLUSIONS: This study provides the first genetic evidence that a GABA(A) receptor is directly involved in a human idiopathic epilepsy. This finding has some importance as GABAergic neurotransmission is known to be involved in epilepsy on the basis of pharmacology, biochemistry and physiopathology data.
Support: This work was funded by the Association pour le Développement de la Recherche sur les Maladies Génétique Neurologiques et Psychiatriques (ADRMGNP), the Association Fran[ccedil]aise contre les Myopathies (AFM), the Association RETINA France, Généthon and the Association pour la Recherche sur la Génétique des Epilepsies (ARGE) sponsored by Sanofi-Synthelabo.