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Three epilepsy-associated GABRG2 missense mutations at the ?+/ß- interface
disrupt GABAA receptor assembly and trafficking by similar mechanisms but to
different extents.

Authors	Huang X, Hernandez CC, Hu N, Macdonald RL
Submitted By	Submitted Externally on 8/5/2014
Status	Published
Journal	Neurobiology of disease
Year	2014
Date Published	8/1/2014
Volume : Pages	68 : 167 - 179
PubMed Reference	24798517
Abstract	We compared the effects of three missense mutations in the GABAA receptor ?2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with a1, ß2, and wildtype or mutant ?2 subunits. The mutations R82Q and P83S were identified in families with genetic epilepsy with febrile seizures plus (GEFS+), and N79S was found in a single patient with generalized tonic-clonic seizures (GTCS). Although all three mutations were located in an N-terminal loop that contributes to the ?+/ß- subunit-subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The ?2(R82Q) and ?2(P83S) subunits had reduced a1ß2?2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, ?2(N79S) subunits were efficiently assembled into GABAA receptors with only minimally altered receptor trafficking, suggesting that N79S was a rare or susceptibility variant rather than an epilepsy mutation. Increased structural variability at assembly motifs was predicted by R82Q and P83S, but not N79S, substitution, suggesting that R82Q and P83S substitutions were less tolerated. Membrane proteins with missense mutations that impair folding and assembly often can be "rescued" by decreased temperatures. We coexpressed wildtype or mutant ?2 subunits with a1 and ß2 subunits and found increased surface and total levels of both wildtype and mutant ?2 subunits after decreasing the incubation temperature to 30°C for 24h, suggesting that lower temperatures increased GABAA receptor stability. Thus epilepsy-associated mutations N79S, R82Q and P83S disrupted GABAA receptor assembly to different extents, an effect that could be potentially rescued by facilitating protein folding and assembly.

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