GABRG2 Mutations Associated with a spectrum of epilepsy syndromes from Generalized Absence Epilepsy to Dravet syndrome

摘要

The GABAA receptor γ2 subunit gene GABRG2 is abundantly expressed in the mammalian brain and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABAA receptor isoforms in the brain. The γ2 subunits play a critical role in GABAA receptor trafficking and clustering at synapses. They reside inside the endoplasmic reticulum (ER) after synthesis where they oligomerize with other binding partners, such as α and β subunits, and further assemble into pentameric receptors. Only correctly assembled receptors can traffick beyond the ER and reach the cell surface and synapses where they conduct chloride ion current when activated by GABA. Mutations in GABRG2 have been associated simple febrile seizures (FS) and with genetic epilepsy syndromes including, childhood absence epilepsy (CAE), generalized epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS)/severe myoclonic epilepsy in infancy (SMEI). The mutations include missense, nonsense and frameshift mutations as well as splice site and deletion mutations. The mutations have been identified in both coding and noncoding sequences like splice sites. In the coding sequence, these mutations are found in multiple locations including the extracellular N-terminus, transmembrane domains and TM3-TM4 intracellular loop. All of these mutations reduced channel function but to different extents and by diverse mechanisms including nonsense mediated mRNA decay (NMD), ER associated protein degradation (ERAD), dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death and gating defects. We conclude that the epilepsy phenotypic heterogeneity associated with GABRG2 mutations may be related to the extent of the reduction of GABAA receptor channel function and the differential dominant negative suppression as well to toxicity related to the metabolism of mutant subunit proteins resulting from each mutant γ2 subunit in addition to different genetic backgrounds.