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Human Molecular Genetics Advance Access originally published online on April 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 13 1315-1319
DOI: 10.1093/hmg/ddh146
Human Molecular Genetics, Vol. 13, No. 13 © Oxford University Press 2004; all rights reserved

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

Leanne M. Dibbens1,2,*,{dagger}, Hua-Jun Feng4,{dagger}, Michaella C. Richards1, Louise A. Harkin1,2, Bree L. Hodgson1, Darren Scott1, Misty Jenkins6, Steven Petrou6, Grant R. Sutherland1,2, Ingrid E. Scheffer5, Samuel F. Berkovic5, Robert L. Macdonald4 and John C. Mulley1,3

1Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia, 2Department of Paediatrics and 3Department of Molecular Biosciences, University of Adelaide, South Australia, Australia, 4Departments of Neurology, Molecular Physiology and Biophysics and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 5Epilepsy Research Institute and Department of Medicine (Neurology), University of Melbourne and Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia and 6Department of Physiology, University of Melbourne, Victoria, Australia

Received February 6, 2004; Accepted April 20, 2004

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, {alpha}1ß2S{delta} 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.

* To whom correspondence should be addressed at: Department of Genetic Medicine, Women's and Children's Hospital/Bionomics Ltd, 31 Dalgleish St Thebarton, South Australia 5031, Australia. Tel: +61 883546119; Fax: +61 883546160; Email: ldibbens{at}bionomics.com.au


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