GRIA3, encoding glutamate ionotropic receptor AMPA type 3 (GluA3), is an X-chromosomal gene. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, of which GluA3 is a subunit, mediate fast excitatory neurotransmission in the brain. These receptors assemble as homo-or heteromers from subunits encoded by GRIA1-GRIA4 genes, and their function is crucial for normal brain activity [1,2,3,4].

Functional studies on GRIA3 variants in patients with neurodevelopmental disorders (NDD) have provided insights into its role. Missense and frameshift variants in GRIA3 were evaluated electrophysiologically. Many variants altered receptor function, showing loss-of-function or gain-of-function properties. Loss-of-function variants in male patients were often de novo or hemizygous, inherited from healthy mothers, while affected females had mostly de novo heterozygous gain-of-function variants. Gain-of-function variants were associated with more severe outcomes such as younger seizure onset, hypertonia, and movement disorders like hyperekplexia. Loss-of-function variants led to older seizure onset, hypotonia, and sleeping disturbances [1]. In a male patient with a gain-of-function GRIA3 variant, carbamazepine, which inhibits glutamate release, ameliorated seizures and hypertonia, suggesting that drugs suppressing glutamatergic neurotransmission may be useful for GRIA3-related NDDs [4].

In conclusion, GRIA3 is essential for normal excitatory neurotransmission in the brain. Studies on its variants in patients have revealed its role in neurodevelopmental disorders. The distinct phenotypes associated with gain-of-function and loss-of-function variants, along with the response to drugs targeting glutamatergic neurotransmission, provide important directions for understanding the disease mechanisms and potential treatments related to GRIA3-associated NDDs.

References:

1. Rinaldi, Berardo, Bayat, Allan, Zachariassen, Linda G, Shi, Yun Stone, Kristensen, Anders S. . Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. In Brain : a journal of neurology, 147, 1837-1855. doi:10.1093/brain/awad403. https://pubmed.ncbi.nlm.nih.gov/38038360/

2. Okano, Satomi, Makita, Yoshio, Miyamoto, Akie, Yanagi, Kumiko, Kaname, Tadashi. 2023. GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy. In Human genome variation, 10, 4. doi:10.1038/s41439-023-00232-1. https://pubmed.ncbi.nlm.nih.gov/36726007/

3. Martinez-Esteve Melnikova, Anastasia, Pijuan, Jordi, Aparicio, Javier, Hoenicka, Janet, San Antonio-Arce, Victoria. 2022. The p.Glu787Lys variant in the GRIA3 gene causes developmental and epileptic encephalopathy mimicking structural epilepsy in a female patient. In European journal of medical genetics, 65, 104442. doi:10.1016/j.ejmg.2022.104442. https://pubmed.ncbi.nlm.nih.gov/35093607/

4. Hamanaka, Kohei, Miyoshi, Keita, Sun, Jia-Hui, Miyatake, Satoko, Matsumoto, Naomichi. 2022. Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant. In Human genetics, 141, 283-293. doi:10.1007/s00439-021-02416-7. https://pubmed.ncbi.nlm.nih.gov/35031858/