Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/149060
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dc.contributor.authorHannan, Saaden_US
dc.contributor.authorAffandi, Aida H. B.en_US
dc.contributor.authorMinere, Marielleen_US
dc.contributor.authorJones, Charlotteen_US
dc.contributor.authorGoh, Pollyannaen_US
dc.contributor.authorWarnes, Garyen_US
dc.contributor.authorPopp, Bernten_US
dc.contributor.authorTrollmann, Reginaen_US
dc.contributor.authorNizetic, Deanen_US
dc.contributor.authorSmart, Trevor G.en_US
dc.date.accessioned2021-05-18T09:15:40Z-
dc.date.available2021-05-18T09:15:40Z-
dc.date.issued2020-
dc.identifier.citationHannan, 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.2748-19.2020en_US
dc.identifier.issn0270-6474en_US
dc.identifier.urihttps://hdl.handle.net/10356/149060-
dc.description.abstractGABAA 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.en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.language.isoenen_US
dc.relationNMRC/CIRG/1438/2015en_US
dc.relation2015-T2-1-023en_US
dc.relation.ispartofThe Journal of Neuroscienceen_US
dc.rights© 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.en_US
dc.subjectScience::Medicineen_US
dc.titleDifferential coassembly of α1-GABAARs associated with epileptic encephalopathyen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.identifier.doi10.1523/JNEUROSCI.2748-19.2020-
dc.description.versionPublished versionen_US
dc.identifier.pmid32513829-
dc.identifier.scopus2-s2.0-85088237815-
dc.identifier.issue29en_US
dc.identifier.volume40en_US
dc.identifier.spage5518en_US
dc.identifier.epage5530en_US
dc.subject.keywordsα Subunit Varianten_US
dc.subject.keywordsEpilepsyen_US
dc.description.acknowledgementT.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.en_US
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