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Human Molecular Genetics Advance Access published online on April 28, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh146
© 2004 by Oxford University Press
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Article

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

Leanne M. Dibbens 1*, Hua-Jun Feng 2, Michaella C. Richards 3, Louise A. Harkin 4, Bree L. Hodgson 3, Darren Scott 3, Misty Jenkins 5, Steven Petrou 5, Grant R. Sutherland 4, Ingrid E. Scheffer 6, Samuel F. Berkovic 6, Robert L. Macdonald 2, John C. Mulley 7

1 Department of Genetic Medicine, Women's and Children's Hospital/Bionomics Ltd, 31 Dalgleish St Thebarton, South Australia, 5031, Australia; Departments of Paediatrics, University of Adelaide, South Australia, Australia
2 Departments of Neurology, Molecular Physiology and Biophysics and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3 Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia
4 Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia; Departments of Paediatrics, University of Adelaide, South Australia, Australia
5 Department of Physiology, University of Melbourne, Victoria, Australia
6 Epilepsy Research Institute and Department of Medicine (Neurology), University of Melbourne and Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia
7 Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia; Molecular Biosciences, University of Adelaide, South Australia, Australia

* To whom correspondence should be addressed. E-mail: ldibbens{at}bionomics.com.au.


  Abstract

A major challenge in understanding complex idiopathic generalised epilepsies (IGEs) has been the characterisation 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 generalised epilepsy with febrile seizures plus (GEFS+). We also report an Arg220His allele in GABRD which is present in the general population. Compared to wildtype receptors, {alpha}1{beta}2S{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 inhibtion, our results suggest that alteration of this process may contribute to the common generalised epilepsies.


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