title: A GABAA receptor mutation causing generalized epilepsy reduces benzodiazepine receptor binding.
abstract: Understanding the consequences of newly discovered single gene mutations causing human epilepsy has the potential to yield new insights into the underlying mechanisms of this disorder. A mutation of the gamma2 subunit of the GABA(A) receptor, which substitutes glutamine for arginine at position 43 (R43Q) has been found in a familial generalized epilepsy. We tested the hypothesis that individuals affected by the GABRG2(R43Q) mutation have reduced binding to the GABA(A) receptor complex using positron emission tomography (PET) and the benzodiazepine receptor ligand [(11)C]-flumazenil. Fourteen subjects with the GABRG2(R43Q) mutation and 20 controls were studied. Benzodiazepine receptor binding was reduced in subjects with the mutation (mean whole brain binding potential for [(11)C]-flumazenil: GABA(A) mutation 0.66+/-0.1; controls 0.89+/-0.1; P<0.003). The greatest change in benzodiazepine binding occurred anteriorly, with peak differences in insular and anterior cingulate cortices revealed by statistical parametric mapping. Our findings provide in vivo evidence of reduced benzodiazepine receptor binding in subjects with the mutation. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, these findings are likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health Heidelberg, Victoria, Australia.
authors.forename: Marco
authors.initials: M
authors.lastname: Fedi
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Rachel
authors.initials: R
authors.lastname: Mulligan
authors.forename: Henri
authors.initials: H
authors.lastname: Tochon-Danguy
authors.forename: David C
authors.initials: DC
authors.lastname: Reutens
mesh_terms: D000328:Adult; D000368:Aged; D001931:Brain Mapping; D004829:Epilepsy, Generalized / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D005442:Flumazenil / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D049268:Positron-Emission Tomography; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil