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Publication Detail
A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment.
  • Publication Type:
    Journal article
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  • Authors:
    Coombs ID, Ziobro J, Krotov V, Surtees T-L, Cull-Candy SG, Farrant M
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  • Country:
    United States
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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.
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