Differential coassembly of α1-GABAARs associated with epileptic encephalopathy
GABAA receptors (GABAARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an indi...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2021
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| Online Access: | https://hdl.handle.net/10356/149060 |
| _version_ | 1826109969081040896 |
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| author | Hannan, Saad Affandi, Aida H. B. Minere, Marielle Jones, Charlotte Goh, Pollyanna Warnes, Gary Popp, Bernt Trollmann, Regina Nizetic, Dean Smart, Trevor G. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Hannan, Saad Affandi, Aida H. B. Minere, Marielle Jones, Charlotte Goh, Pollyanna Warnes, Gary Popp, Bernt Trollmann, Regina Nizetic, Dean Smart, Trevor G. |
| author_sort | Hannan, Saad |
| collection | NTU |
| description | GABAA receptors (GABAARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren syndrome identified a frameshifting de novo variant in a major GABAAR gene, GABRA1. This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1Lys374Serfs*25. Cell surface expression of mutant murine GABAARs is severely impaired compared with WT, due to retention in the endoplasmic reticulum. Mutant receptors were differentially coexpressed with β3, but not with β2, subunits in mammalian cells. Reduced surface expression was reflected by smaller IPSCs, which may underlie the induction of seizures. The mutant does not have a dominant-negative effect on native neuronal GABAAR expression since GABA current density was unaffected in hippocampal neurons, although mutant receptors exhibited limited GABA sensitivity. To date, the underlying mechanism is unique for epileptogenic variants and involves differential β subunit expression of GABAAR populations, which profoundly affected receptor function and synaptic inhibition. |
| first_indexed | 2024-10-01T02:26:48Z |
| format | Journal Article |
| id | ntu-10356/149060 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:26:48Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1490602023-03-05T16:45:02Z Differential coassembly of α1-GABAARs associated with epileptic encephalopathy Hannan, Saad Affandi, Aida H. B. Minere, Marielle Jones, Charlotte Goh, Pollyanna Warnes, Gary Popp, Bernt Trollmann, Regina Nizetic, Dean Smart, Trevor G. Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine α Subunit Variant Epilepsy GABAA receptors (GABAARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren syndrome identified a frameshifting de novo variant in a major GABAAR gene, GABRA1. This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1Lys374Serfs*25. Cell surface expression of mutant murine GABAARs is severely impaired compared with WT, due to retention in the endoplasmic reticulum. Mutant receptors were differentially coexpressed with β3, but not with β2, subunits in mammalian cells. Reduced surface expression was reflected by smaller IPSCs, which may underlie the induction of seizures. The mutant does not have a dominant-negative effect on native neuronal GABAAR expression since GABA current density was unaffected in hippocampal neurons, although mutant receptors exhibited limited GABA sensitivity. To date, the underlying mechanism is unique for epileptogenic variants and involves differential β subunit expression of GABAAR populations, which profoundly affected receptor function and synaptic inhibition. Ministry of Education (MOE) National Medical Research Council (NMRC) Published version T.G.S. and S.H. were supported by Medical Research Council United Kingdom, Wellcome Trust, and International Rett Syndrome Foundation (3606). D.N. was supported by Singapore National Medical Research Council NMRC/CIRG/1438/2015, Singapore Ministry of Education Academic Research Fund Tier 2 Grant 2015-T2-1-023, and Wellcome Trust “LonDownS Consortium” Strategic Funding Award 098330/Z/12/Z. B.P. was supported by the Deutsche Forschungsgemeinschaft Grant PO2366/2-1. 2021-05-18T09:15:40Z 2021-05-18T09:15:40Z 2020 Journal Article Hannan, S., Affandi, A. H. B., Minere, M., Jones, C., Goh, P., Warnes, G., Popp, B., Trollmann, R., Nizetic, D. & Smart, T. G. (2020). Differential coassembly of α1-GABAARs associated with epileptic encephalopathy. The Journal of Neuroscience, 40(29), 5518-5530. https://dx.doi.org/10.1523/JNEUROSCI.2748-19.2020 0270-6474 https://hdl.handle.net/10356/149060 10.1523/JNEUROSCI.2748-19.2020 32513829 2-s2.0-85088237815 29 40 5518 5530 en NMRC/CIRG/1438/2015 2015-T2-1-023 The Journal of Neuroscience © 2020 The Author(s) (published by Society for Neuroscience). This is an open-access article distributed under the terms of the Creative Commons Attribution License. application/pdf |
| spellingShingle | Science::Medicine α Subunit Variant Epilepsy Hannan, Saad Affandi, Aida H. B. Minere, Marielle Jones, Charlotte Goh, Pollyanna Warnes, Gary Popp, Bernt Trollmann, Regina Nizetic, Dean Smart, Trevor G. Differential coassembly of α1-GABAARs associated with epileptic encephalopathy |
| title | Differential coassembly of α1-GABAARs associated with epileptic encephalopathy |
| title_full | Differential coassembly of α1-GABAARs associated with epileptic encephalopathy |
| title_fullStr | Differential coassembly of α1-GABAARs associated with epileptic encephalopathy |
| title_full_unstemmed | Differential coassembly of α1-GABAARs associated with epileptic encephalopathy |
| title_short | Differential coassembly of α1-GABAARs associated with epileptic encephalopathy |
| title_sort | differential coassembly of α1 gabaars associated with epileptic encephalopathy |
| topic | Science::Medicine α Subunit Variant Epilepsy |
| url | https://hdl.handle.net/10356/149060 |
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