Both authors contributed equally to this study.
Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy
Article first published online: 30 JUN 2011
© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 34, Issue 2, pages 237–249, July 2011
How to Cite
Lachance-Touchette, P., Brown, P., Meloche, C., Kinirons, P., Lapointe, L., Lacasse, H., Lortie, A., Carmant, L., Bedford, F., Bowie, D. and Cossette, P. (2011), Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. European Journal of Neuroscience, 34: 237–249. doi: 10.1111/j.1460-9568.2011.07767.x
- Issue published online: 18 JUL 2011
- Article first published online: 30 JUN 2011
- Received 1 April 2011, revised 3 May 2011, accepted 16 May 2011
- synaptic inhibition
Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion-channel genes being implicated, including those encoding the GABAA receptor. Here, we evaluated the frequency of additional mutations in the GABAA receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25-bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABAA receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals.