Differential protein structural disturbances and suppression of assembly partners produced by nonsense GABRG2 epilepsy mutations: implications for disease phenotypic heterogeneity.

摘要: Mutations in GABAA receptor subunit genes are frequently associated with epilepsy, and nonsense mutations GABRG2 several epilepsy syndromes including childhood absence generalized tonic clonic seizures the epileptic encephalopathy, Dravet syndrome. The molecular basis for phenotypic heterogeneity of is unclear. Here we focused on three (GABRG2(R136*), GABRG2(Q390*) GABRG2(W429*)) epilepsies different severities. Structural modeling structure-based analysis indicated that surface wild-type γ2 was naturally hydrophobic, which suitable to be buried cell membrane. Different mutant subunits had stabilities interactions their binding partners because they adopted conformations hydrophobicities tendency dimerize. We utilized flow cytometry biochemical approaches combination lifted whole patch-clamp recordings. demonstrated truncated no minimal expression unchanged or reduced partnering subunits. amplitudes GABA-evoked currents from α1β2γ2(R136*), α1β2γ2(Q390*) α1β2γ2(W429*) receptors were compared α1β2γ2 but differentially levels. This thus suggests differential protein structure disturbances correlated disease severity.