Journal article
Expanded molecular pathomechanisms of GlyR α2 subunit variants in neurodevelopmental disorders and epileptic encephalopathy
Scientific Reports, Vol.Advanced access
24-Jul-2026
Abstract
Rare genetic variants in the glycine receptor (GlyR) α2 subunit gene ( GLRA2 ) are associated with autism spectrum disorder, developmental delay, and intellectual disability, often accompanied by microcephaly, language delay or epilepsy. We report detailed structure-function analyses of nine previously uncharacterised GlyR α2 missense variants, including a novel de novo change (p.S285P) linked to epileptic encephalopathy. Using molecular modelling/dynamics simulations, electrophysiology, and immunocytochemistry, we assessed effects of GlyR α2 variants on agonist potency, efficacy, channel gating, and cell-surface trafficking. Five missense variants caused a partial loss-of-function via reduced glycine potency (p.F20S, p.A261T, p.R418Q), reduced glycine efficacy (p.F20S), or faster channel deactivation (p.R323C, p.P369T). By contrast, p.R225C abolished cell-surface expression resulting in a complete loss-of-function . The p.A261T variant also significantly reduced picrotoxin binding, resolving ambiguity in GlyR-PTX interaction models. Additional variants showed an alteration-of-function (p.I232M) or a gain-of-function (p.S285P), combining reduced glycine efficacy with increased potency and spontaneous leak currents. Two variants within the intracellular M3-M4 domain (p.R323C and p.P369T) had enhanced channel deactivation consistent with a loss-of-function , while p.P373L showed no detectable functional deficit. These findings expand the clinical and mechanistic spectrum of GlyR α2 variants, identify a key determinant of picrotoxin binding, and highlight unresolved roles of intracellular protein-protein interaction motifs in GlyR α2 function.
Details
- Title
- Expanded molecular pathomechanisms of GlyR α2 subunit variants in neurodevelopmental disorders and epileptic encephalopathy
- Authors
- Sean D. Fraser - University of the Sunshine CoastAnna-Lena Wiessler - Universitätsklinikum WürzburgWing Yan Jessica Choi - The University of SydneyNatascha Schaefer - Universitätsklinikum WürzburgPatrick Sutton - The University of QueenslandStéphanie Arpin - InsermPaul Gueguen - InsermMegan L. O’Mara - The University of QueenslandRobert J. Vandenberg - The University of SydneyCarmen Villmann - Universitätsklinikum WürzburgRobert J. Harvey (Corresponding Author) - University of the Sunshine Coast
- Publication details
- Scientific Reports, Vol.Advanced access
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/s41598-026-61911-x
- ISSN
- 2045-2322
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Grants
- Microproteins: from invisibility to relevance in neuroscience and cancer, 0980029932, University of the Sunshine Coast (Australia, Sunshine Coast) - UniSC
- Grant note
- Queensland-Bavaria Collaborative Research Program Development Grant (QLDBAVDEV25023) to RJH and NS, and a Deutsche Forschungsgemeinschaft grant (VI586) to CV.
- Organisation Unit
- School of Health - Biomedicine; School of Health; Thompson Institute
- Language
- English
- Record Identifier
- 991249390602621
- Output Type
- Journal article
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