GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

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dc.contributor.authorDibbens, L.
dc.contributor.authorFeng, H.
dc.contributor.authorRichards, M.
dc.contributor.authorHarkin, L.
dc.contributor.authorHodgson, B.
dc.contributor.authorScott, D.
dc.contributor.authorJenkins, M.
dc.contributor.authorPetrou, S.
dc.contributor.authorSutherland, G.
dc.contributor.authorScheffer, I.
dc.contributor.authorBerkovic, S.
dc.contributor.authorMcdonald, R.
dc.contributor.authorMulley, J.
dc.date.issued2004
dc.description.abstractA 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 δ 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, α1β2Sδ GABAA receptors containing δ 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 d 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.
dc.description.statementofresponsibilityLeanne M. Dibbens, Hua-Jun Feng, Michaella C. Richards, Louise A. Harkin, Bree L. Hodgson, Darren Scott, Misty Jenkins, Steven Petrou, Grant R. Sutherland, Ingrid E. Scheffer, Samuel F. Berkovic, Robert L. Macdonald and John C. Mulley
dc.identifier.citationHuman Molecular Genetics, 2004; 13(13):1315-1319
dc.identifier.doi10.1093/hmg/ddh146
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.urihttp://hdl.handle.net/2440/7342
dc.language.isoen
dc.publisherOxford Univ Press
dc.rightsCopyright © Oxford University Press 2004; all rights reserved
dc.source.urihttps://doi.org/10.1093/hmg/ddh146
dc.subjectSynaptic Membranes
dc.subjectHumans
dc.subjectEpilepsy, Generalized
dc.subjectSeizures, Febrile
dc.subjectGenetic Predisposition to Disease
dc.subjectReceptors, GABA-A
dc.subjectAmino Acid Substitution
dc.subjectPedigree
dc.subjectHeterozygote
dc.subjectHomozygote
dc.subjectMultifactorial Inheritance
dc.subjectPoint Mutation
dc.subjectFemale
dc.subjectMale
dc.titleGABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies
dc.typeJournal article
pubs.publication-statusPublished

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