Currently, a total of 19 different GABRG2 disease-causing mutations have been reported (including this study), consisting of 8 missense, 4 nonsense, 4 frameshifts, 2 splice-sites, and 1 deletion (figure 2). The high rate of truncating mutations (11/19, 57%), strengthened by this study, strongly suggests that haploinsufficiency resulting in loss of function of GABAA receptor γ2 subunit underlies GABRG2-related seizure phenotypes. This is concordant with numerous in vitro functional assays showing that GABRG2 mutations resulted in mRNA degradation by NMD, the translation of proteins retained in the endoplasmic reticulum with impaired surface-expression, or dysfunctional channel properties of GABAA receptors20,25,31,32,36–38 (for review, see references 15 and 16). However, 2 recent in vivo studies using Gln390*-Gabrg2 knock-in mice showed that dominant-negative effects on wild-type γ2 and partner subunits also certainly participated to reduce GABA-evoked currents.33,39 A reduction in cortical synaptic GABAergic inhibition was confirmed to cause seizures in another p.Arg82Gln-Gabrg2 knock-in mouse model.40 Nevertheless, the link between dysfunctional GABAA receptors and seizures is still poorly understood.
