Journal Article

<i>GABRD</i> encoding a protein for extra- or peri-synaptic GABA<sub>A</sub> receptors is a susceptibility locus for generalized epilepsies

Leanne 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

in Human Molecular Genetics

Volume 13, issue 13, pages 1315-1319
Published in print July 2004 | ISSN: 0964-6906
Published online April 2004 | e-ISSN: 1460-2083 | DOI:
GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

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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 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 δ 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.

Journal Article.  3178 words.  Illustrated.

Subjects: Genetics and Genomics

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