title: Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy.
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 GABA(A) receptor. Here, we evaluated the frequency of additional mutations in the GABA(A) 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 GABA(A) 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.
authors.affiliation: Centre for Excellence in Neuromics of University of Montreal, CHUM Research Center, 1560 Sherbrooke est, Montreal, QC, Canada H2L 4M1.
authors.forename: Pamela
authors.initials: P
authors.lastname: Lachance-Touchette
authors.forename: Patricia
authors.initials: P
authors.lastname: Brown
authors.forename: Caroline
authors.initials: C
authors.lastname: Meloche
authors.forename: Peter
authors.initials: P
authors.lastname: Kinirons
authors.forename: Line
authors.initials: L
authors.lastname: Lapointe
authors.forename: Hélène
authors.initials: H
authors.lastname: Lacasse
authors.forename: Anne
authors.initials: A
authors.lastname: Lortie
authors.forename: Lionel
authors.initials: L
authors.lastname: Carmant
authors.forename: Fiona
authors.initials: F
authors.lastname: Bedford
authors.forename: Derek
authors.initials: D
authors.lastname: Bowie
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics*; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: C546240:GABRA1 protein, human; C546279:GABRG2 protein, human; D021122:Protein Subunits; D011963:Receptors, GABA-A