Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy

Authors

  • Pamela Lachance-Touchette,

    1. Centre for Excellence in Neuromics of University of Montreal (CENUM), CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1
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    • Both authors contributed equally to this study.

  • Patricia Brown,

    1. Department of Pharmacology & Therapeutics, McGill University, Bellini Life Sciences Complex, Room 164, 3649 Sir William Osler Promenade, Montreal, QC, Canada H3G 0B1
    2. Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
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    • Both authors contributed equally to this study.

  • Caroline Meloche,

    1. Centre for Excellence in Neuromics of University of Montreal (CENUM), CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1
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  • Peter Kinirons,

    1. Centre for Excellence in Neuromics of University of Montreal (CENUM), CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1
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  • Line Lapointe,

    1. Centre for Excellence in Neuromics of University of Montreal (CENUM), CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1
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  • Hélène Lacasse,

    1. Centre for Excellence in Neuromics of University of Montreal (CENUM), CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1
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  • Anne Lortie,

    1. Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC, Canada
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  • Lionel Carmant,

    1. Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC, Canada
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  • Fiona Bedford,

    1. Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
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  • Derek Bowie,

    1. Department of Pharmacology & Therapeutics, McGill University, Bellini Life Sciences Complex, Room 164, 3649 Sir William Osler Promenade, Montreal, QC, Canada H3G 0B1
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  • Patrick Cossette

    1. Centre for Excellence in Neuromics of University of Montreal (CENUM), CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1
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Dr Derek Bowie and Dr Patrick Cossette, as above.
E-mails: derek.bowie@mcgill.ca and patrick.cossette@umontreal.ca

Abstract

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.

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