Expanded molecular pathomechanisms of GlyR α2 subunit variants in neurodevelopmental disorders and epileptic encephalopathy
5 affiliations
- 1School of Health, University of the Sunshine Coast
- 2Institute for Clinical Neurobiology, University Hospital Würzburg
- 3School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney
- 4Australian Institute for Bioengineering and Nanotechnology, University of Queensland
- 5Laboratoire de Génétique Moléculaire et INSERM U1253, CHRU de Tours - Hôpital Bretonneau
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.
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BibTeX
@article{fraser2026expanded,
title = {{Expanded molecular pathomechanisms of GlyR α2 subunit variants in neurodevelopmental disorders and epileptic encephalopathy}},
author = {Sean D. Fraser and Anna-Lena Wiessler and Wing Yan Jessica Choi and Natascha Schaefer and Patrick Sutton and Stéphanie Arpin and Paul Gueguen and Megan L. O’Mara and Robert J. Vandenberg and Carmen Villmann and Robert J. Harvey},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-61911-x},
url = {https://doi.org/10.1038/s41598-026-61911-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - Expanded molecular pathomechanisms of GlyR α2 subunit variants in neurodevelopmental disorders and epileptic encephalopathy
AU - Sean D. Fraser
AU - Anna-Lena Wiessler
AU - Wing Yan Jessica Choi
AU - Natascha Schaefer
AU - Patrick Sutton
AU - Stéphanie Arpin
AU - Paul Gueguen
AU - Megan L. O’Mara
AU - Robert J. Vandenberg
AU - Carmen Villmann
AU - Robert J. Harvey
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-61911-x
UR - https://doi.org/10.1038/s41598-026-61911-x
AB - 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.
SN - 2045-2322
ER -