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

We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 subunits. The mutations R82Q and P83S were identified in families with genetic epilepsy with...
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Autor*in:	Xuan Huang [verfasserIn] Ciria C. Hernandez [verfasserIn] Ningning Hu [verfasserIn] Robert L. Macdonald [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2014

Schlagwörter:	GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function

Übergeordnetes Werk:	In: Neurobiology of Disease - Elsevier, 2021, 68(2014), Seite 167-179
Übergeordnetes Werk:	volume:68 ; year:2014 ; pages:167-179

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.nbd.2014.04.015

Katalog-ID:	DOAJ056915217

Internformat


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520			\|a We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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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650		4	\|a Genetic generalized epilepsy
650		4	\|a GABRG2(N79S) mutation
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650		4	\|a Loss of function
653		0	\|a Neurosciences. Biological psychiatry. Neuropsychiatry
700	0		\|a Ciria C. Hernandez \|e verfasserin \|4 aut
700	0		\|a Ningning Hu \|e verfasserin \|4 aut
700	0		\|a Robert L. Macdonald \|e verfasserin \|4 aut
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912			\|a GBV_ILN_4313
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publishDate	2014
allfields	10.1016/j.nbd.2014.04.015 doi (DE-627)DOAJ056915217 (DE-599)DOAJe7134dabba8840d394e0f5edb5592d64 DE-627 ger DE-627 rakwb eng RC321-571 Xuan Huang verfasserin aut Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents 2014 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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. GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function Neurosciences. Biological psychiatry. Neuropsychiatry Ciria C. Hernandez verfasserin aut Ningning Hu verfasserin aut Robert L. Macdonald verfasserin aut In Neurobiology of Disease Elsevier, 2021 68(2014), Seite 167-179 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:68 year:2014 pages:167-179 https://doi.org/10.1016/j.nbd.2014.04.015 kostenfrei https://doaj.org/article/e7134dabba8840d394e0f5edb5592d64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996114001041 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 68 2014 167-179
spelling	10.1016/j.nbd.2014.04.015 doi (DE-627)DOAJ056915217 (DE-599)DOAJe7134dabba8840d394e0f5edb5592d64 DE-627 ger DE-627 rakwb eng RC321-571 Xuan Huang verfasserin aut Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents 2014 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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. GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function Neurosciences. Biological psychiatry. Neuropsychiatry Ciria C. Hernandez verfasserin aut Ningning Hu verfasserin aut Robert L. Macdonald verfasserin aut In Neurobiology of Disease Elsevier, 2021 68(2014), Seite 167-179 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:68 year:2014 pages:167-179 https://doi.org/10.1016/j.nbd.2014.04.015 kostenfrei https://doaj.org/article/e7134dabba8840d394e0f5edb5592d64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996114001041 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 68 2014 167-179
allfields_unstemmed	10.1016/j.nbd.2014.04.015 doi (DE-627)DOAJ056915217 (DE-599)DOAJe7134dabba8840d394e0f5edb5592d64 DE-627 ger DE-627 rakwb eng RC321-571 Xuan Huang verfasserin aut Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents 2014 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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. GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function Neurosciences. Biological psychiatry. Neuropsychiatry Ciria C. Hernandez verfasserin aut Ningning Hu verfasserin aut Robert L. Macdonald verfasserin aut In Neurobiology of Disease Elsevier, 2021 68(2014), Seite 167-179 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:68 year:2014 pages:167-179 https://doi.org/10.1016/j.nbd.2014.04.015 kostenfrei https://doaj.org/article/e7134dabba8840d394e0f5edb5592d64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996114001041 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 68 2014 167-179
allfieldsGer	10.1016/j.nbd.2014.04.015 doi (DE-627)DOAJ056915217 (DE-599)DOAJe7134dabba8840d394e0f5edb5592d64 DE-627 ger DE-627 rakwb eng RC321-571 Xuan Huang verfasserin aut Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents 2014 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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. GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function Neurosciences. Biological psychiatry. Neuropsychiatry Ciria C. Hernandez verfasserin aut Ningning Hu verfasserin aut Robert L. Macdonald verfasserin aut In Neurobiology of Disease Elsevier, 2021 68(2014), Seite 167-179 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:68 year:2014 pages:167-179 https://doi.org/10.1016/j.nbd.2014.04.015 kostenfrei https://doaj.org/article/e7134dabba8840d394e0f5edb5592d64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996114001041 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 68 2014 167-179
allfieldsSound	10.1016/j.nbd.2014.04.015 doi (DE-627)DOAJ056915217 (DE-599)DOAJe7134dabba8840d394e0f5edb5592d64 DE-627 ger DE-627 rakwb eng RC321-571 Xuan Huang verfasserin aut Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents 2014 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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. GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function Neurosciences. Biological psychiatry. Neuropsychiatry Ciria C. Hernandez verfasserin aut Ningning Hu verfasserin aut Robert L. Macdonald verfasserin aut In Neurobiology of Disease Elsevier, 2021 68(2014), Seite 167-179 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:68 year:2014 pages:167-179 https://doi.org/10.1016/j.nbd.2014.04.015 kostenfrei https://doaj.org/article/e7134dabba8840d394e0f5edb5592d64 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996114001041 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 68 2014 167-179
language	English
source	In Neurobiology of Disease 68(2014), Seite 167-179 volume:68 year:2014 pages:167-179
sourceStr	In Neurobiology of Disease 68(2014), Seite 167-179 volume:68 year:2014 pages:167-179
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function Neurosciences. Biological psychiatry. Neuropsychiatry
isfreeaccess_bool	true
container_title	Neurobiology of Disease
authorswithroles_txt_mv	Xuan Huang @@aut@@ Ciria C. Hernandez @@aut@@ Ningning Hu @@aut@@ Robert L. Macdonald @@aut@@
publishDateDaySort_date	2014-01-01T00:00:00Z
hierarchy_top_id	268125414
id	DOAJ056915217
language_de	englisch
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Membrane proteins with missense mutations that impair folding and assembly often can be “rescued” by decreased temperatures. We coexpressed wildtype or mutant γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, suggesting that lower temperatures increased GABAA receptor stability. 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callnumber-first	R - Medicine
author	Xuan Huang
spellingShingle	Xuan Huang misc RC321-571 misc GABAA receptors misc Genetic generalized epilepsy misc GABRG2(N79S) mutation misc GABRG2(R82Q) mutation misc GABRG2(P83S) mutation misc Loss of function misc Neurosciences. Biological psychiatry. Neuropsychiatry Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents
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topic_title	RC321-571 Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents GABAA receptors Genetic generalized epilepsy GABRG2(N79S) mutation GABRG2(R82Q) mutation GABRG2(P83S) mutation Loss of function
topic	misc RC321-571 misc GABAA receptors misc Genetic generalized epilepsy misc GABRG2(N79S) mutation misc GABRG2(R82Q) mutation misc GABRG2(P83S) mutation misc Loss of function misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_unstemmed	misc RC321-571 misc GABAA receptors misc Genetic generalized epilepsy misc GABRG2(N79S) mutation misc GABRG2(R82Q) mutation misc GABRG2(P83S) mutation misc Loss of function misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_browse	misc RC321-571 misc GABAA receptors misc Genetic generalized epilepsy misc GABRG2(N79S) mutation misc GABRG2(R82Q) mutation misc GABRG2(P83S) mutation misc Loss of function misc Neurosciences. Biological psychiatry. Neuropsychiatry
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title	Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents
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title_full	Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents
author_sort	Xuan Huang
journal	Neurobiology of Disease
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author_browse	Xuan Huang Ciria C. Hernandez Ningning Hu Robert L. Macdonald
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author-letter	Xuan Huang
doi_str_mv	10.1016/j.nbd.2014.04.015
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title_sort	three epilepsy-associated gabrg2 missense mutations at the γ+/β− interface disrupt gabaa receptor assembly and trafficking by similar mechanisms but to different extents
callnumber	RC321-571
title_auth	Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents
abstract	We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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.
abstractGer	We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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.
abstract_unstemmed	We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, 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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title_short	Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents
url	https://doi.org/10.1016/j.nbd.2014.04.015 https://doaj.org/article/e7134dabba8840d394e0f5edb5592d64 http://www.sciencedirect.com/science/article/pii/S0969996114001041 https://doaj.org/toc/1095-953X
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up_date	2024-07-03T23:30:04.596Z
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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 γ+/β− subunit–subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(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 γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30 °C for 24 h, suggesting that lower temperatures increased GABAA receptor stability. 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Three epilepsy-associated GABRG2 missense mutations at the γ+/β− interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents

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