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Genetic epilepsy is a common disorder with phenotypic variation, but the basis for the variation is unknown. Comparing the molecular pathophysiology of mutations in the same epilepsy gene may provide mechanistic insights into the phenotypic heterogeneity. GABRG2 is an established epilepsy gene, and mutations in it produce epilepsy syndromes with varying severities. The disease phenotype in some cases may be caused by simple loss of subunit function (functional haploinsufficiency), while others may be caused by loss-of-function plus dominant negative suppression and other cellular toxicity. Detailed molecular defects and the corresponding seizures and related comorbidities resulting from haploinsufficiency and dominant negative mutations, however, have not been compared. Here we compared two mouse models of GABRG2 loss-of-function mutations associated with epilepsy with different severities, Gabrg2 +/Q390X knockin (KI) and Gabrg2 +/- knockout (KO) mice. Heterozygous Gabrg2 +/Q390X KI mice are associated with a severe epileptic encephalopathy due to a dominant negative effect of the mutation, while heterozygous Gabrg2 +/- KO mice are associated with mild absence epilepsy due to simple haploinsufficiency. Unchanged at the transcriptional level, KI mice with severe epilepsy had neuronal accumulation of mutant γ2 subunits, reduced remaining functional wild-type subunits in dendrites and synapses, while KO mice with mild epilepsy had no intracellular accumulation of the mutant subunits and unaffected biogenesis of the remaining wild-type subunits. Consequently, KI mice with dominant negative mutations had much less wild-type receptor expression, more severe seizures and behavioural comorbidities than KO mice. This work provides insights into the pathophysiology of epilepsy syndrome heterogeneity and designing mechanism-based therapies.

human molecular genetics online/human molecular genetics

Differential molecular and behavioural alterations in mouse models of<i><i>GABRG2</i></i>haploinsufficiency versus dominant negative mutations associated with human epilepsy

Differential molecular and behavioural alterations in mouse models ofGABRG2haploinsufficiency versus dominant negative mutations associated with human epilepsy