Coombs, Ian D;
Ziobro, Julie;
Krotov, Volodymyr;
Surtees, Taryn-Leigh;
Cull-Candy, Stuart G;
Farrant, Mark;
(2022)
A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment.
Epilepsia
, 63
(12)
e156-e163.
10.1111/epi.17419.
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Epilepsia - 2022 - Coombs - A gain‐of‐function GRIA2 variant associated with neurodevelopmental delay and seizures .pdf Download (10MB) | Preview |
Abstract
AMPA-type glutamate receptors (AMPARs) are ligand-gated cationic channels formed from combinations of GluA1-4 subunits. Pathogenic variants of GRIA1-4 have been described in patients with developmental delay, intellectual disability, autism spectrum disorder, and seizures, with GRIA2 variants typically causing AMPAR loss-of-function. Here we identify a novel, heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V, NM_001083619.1) in a one-year-old boy with epilepsy, developmental delay and failure-to-thrive. We made patch-clamp recordings to compare the functional and pharmacological properties of variant and wild-type receptors expressed in HEK293 cells, with- and without the transmembrane AMPAR regulatory protein (TARP) γ2. This showed GluA2 A643V-containing AMPARs to exhibit a novel gain-of-function, with greatly slowed deactivation, markedly reduced desensitization and increased glutamate sensitivity. Perampanel, an anti-seizure AMPAR negative allosteric modulator, was able to fully block GluA2 A643V/γ2 currents, suggesting potential therapeutic efficacy. The subsequent introduction of perampanel to the patient's treatment regimen was associated with a marked reduction in seizure burden, a resolution of failure-to-thrive, and clear developmental gains. Our study reveals that GRIA2 disorder can be caused by a gain-of-function variant, and both predicts and suggests the therapeutic efficacy of perampanel. Perampanel may prove beneficial for patients with other gain-of-function GRIA variants.
| Type: | Article |
|---|---|
| Title: | A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/epi.17419 |
| Publisher version: | https://doi.org/10.1111/epi.17419 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10156565 |
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