A gain‐of‐function GRIA2 variant associated with neurodevelopmental delay and seizures: Functional characterization and targeted treatment

Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-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 1-year-old boy with epilepsy, developmental delay, and failure to thrive. We made patchclamp 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 γ2. This showed GluA2 A643Vcontaining AMPARs to exhibit a novel gain of function, with greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity. Perampanel, an antiseizure 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.

Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures

“…In the present study, a major finding was that ELS-TRAPed neurons undergo unique changes in AMPAR function that are not shared by surrounding cells. Specifically, in hippocampal CA1, only a subset of neurons expressed tdT abnormalities, including intellectual disability, autism spectrum disorder, seizures, and developmental epileptic encephalopathy (63)(64)(65). Transgenic mouse models with transcriptional mutations resulting in loss of GluA2 expression and function reveal neurons with inwardly rectifying currents similar to those observed in our study and mice show behavioral deficits and seizures (63,66,67).…”

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model

“…Perhaps the most notable of these processes is the enrichment of “Tube Development.” While many of the included genes in this set pertain to processes associated with angiogenesis and uretic bud formation, it should be noted that many of these markers have dual roles reliant on context. Specifically, the expression of mRNAs such as SFRP2 and GRIA2 in this cluster may favor smaller sub-processes related to the neural tube or neural development processes, such as “Gliogenesis” ( 114 – 116 ).…”

Identification of genetic causes in children with unexplained epilepsy based on trio‐whole exome sequencing

“…However, the effects on currents greatly varied among GRIA2 variants, with striking differences even when comparing nearby residues 50 . The molecular findings of GRIA2 variants made targeted and effective treatments 51 . Therefore, genetic results can improve selection of anti‐epileptic drugs and precise therapeutic regimens.…”