ArticleHuman genetics2022
Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant.
Article in Human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 10 citations in OpenAlex.
- Review
- Transcriptomic Profiling of Zebrafish Mutant forInternational journal of molecular sciences · 2025Article
- Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes.Brain : a journal of neurology · 2024Article
- Clinical and functional consequences of GRIA variants in patients with neurological diseases.Cellular and molecular life sciences : CMLS · 2023Article
- Biallelic structural variations withinLife science alliance · 2023Article
- GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy.Human genome variation · 2023Article
- Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human.Molecular psychiatry · 2022Article
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Authors and funding
20 authors at 10 institutions in 5 countries.
Funding
Abstract
GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.
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