title: GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.
abstract: A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.
authors.affiliation: Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia. ldibbens@bionomics.com.au
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Feng
authors.forename: Michaella C
authors.initials: MC
authors.lastname: Richards
authors.forename: Louise A
authors.initials: LA
authors.lastname: Harkin
authors.forename: Bree L
authors.initials: BL
authors.lastname: Hodgson
authors.forename: Darren
authors.initials: D
authors.lastname: Scott
authors.forename: Misty
authors.initials: M
authors.lastname: Jenkins
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.forename: Grant R
authors.initials: GR
authors.lastname: Sutherland
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Robert L
authors.initials: RL
authors.lastname: Macdonald
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D010375:Pedigree; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics / Q000503:physiopathology; D013570:Synaptic Membranes / Q000473:pathology
chemical_list: C464500:GABRD protein, human; D011963:Receptors, GABA-A