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Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

Abstract

Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the α1 subunit of the γ-aminobutyric acid receptor subtype A (GABAA), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABAA receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.

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Figure 1: A large French Canadian kindred affected with JME.
Figure 2: Electroencephalogram abnormalities found in affected members of the family.
Figure 3: The Ala322Asp mutation in GABRA1 is located in a highly conserved domain of the protein.
Figure 4: Effect of the Ala322Asp mutation on GABA-evoked currents in transfected HEK 293 cells.
Figure 5: Effect of the Ala322Asp mutation on the maximum response and affinity of the GABAA receptors.

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Acknowledgements

We thank the family for participating in this study, and G. Geoffroy, who brought them to our attention. We also thank W. Ju for assistance in cell transfection experiments, and C. Darmond-Zwaig and T. J. Hudson from the Genome Centre of the Montreal General Hospital. P.C. is funded by a fellowship from the Canadian Institute for Health Research (CIHR), under the clinical-scientist program. G.A.R. is supported by the CIHR.

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Correspondence to Guy A. Rouleau.

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Cossette, P., Liu, L., Brisebois, K. et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 31, 184–189 (2002). https://doi.org/10.1038/ng885

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