GRIN3A, which encodes the GluN3A subunit of N-methyl-D-aspartate receptors (NMDARs), endows NMDARs with unique biophysical, trafficking, and signaling properties. NMDARs play a crucial role in synaptic plasticity in the brain. GluN3A-NMDARs are expressed during postnatal development, where they are thought to regulate the refinement of neural circuits by inhibiting synapse maturation and stabilization. They also operate in adult brains to control various behaviors [4].

In a study on prostate cancer, GRIN3A was identified as a biomarker associated with a cribriform pattern and poor prognosis. Its expression was significantly higher in cribriform pattern samples compared to non-cribriform Gleason pattern 4 samples, both within the same patient and between different patients, and was also associated with biochemical recurrence [1]. A study on Alzheimer's disease found that decreased NR3A (encoded by GRIN3A) is correlated with tauopathy and loss of postsynaptic function in the hippocampal region [2]. In Arab children with acute lymphoblastic leukemia, a GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis, as variant allele carriers had to stop dexamethasone therapy earlier [3]. A polymorphism of the GRIN3A gene may play a role in Kawasaki disease pathogenesis, as the rs7849782 genetic variant was associated with a lower rate of coronary artery aneurysm formation in KD patients [5].

In conclusion, GRIN3A is essential for the normal function of NMDARs, playing a key role in neural circuit refinement during development and various behaviors in adulthood. Model-based research, including the analysis of genetic polymorphisms in different patient cohorts, has revealed its associations with multiple diseases, such as prostate cancer, Alzheimer's disease, osteonecrosis in leukemia patients, and Kawasaki disease, providing insights into disease mechanisms and potential biomarkers.

References:

1. Bogaard, Mari, Strømme, Jonas M, Kidd, Susanne G, Skotheim, Rolf I, Axcrona, Ulrika. 2024. GRIN3A: A biomarker associated with a cribriform pattern and poor prognosis in prostate cancer. In Neoplasia (New York, N.Y.), 55, 101023. doi:10.1016/j.neo.2024.101023. https://pubmed.ncbi.nlm.nih.gov/38944914/

2. Lee, Sang-Eun, Park, Soomin, Kang, Rian, Chang, Sunghoe, Park, Jong-Chan. 2024. Hippocampal tau-induced GRIN3A deficiency in Alzheimer's disease. In FEBS open bio, 14, 2059-2071. doi:10.1002/2211-5463.13904. https://pubmed.ncbi.nlm.nih.gov/39396906/

3. Zgheib, Nathalie K, El-Khoury, Habib, Maamari, Dimitri, Saab, Raya, Muwakkit, Samar A. 2021. A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia. In Personalized medicine, 18, 431-439. doi:10.2217/pme-2020-0167. https://pubmed.ncbi.nlm.nih.gov/34406079/

4. Murillo, Alvaro, Navarro, Ana I, Puelles, Eduardo, Petros, Timothy J, Pérez-Otaño, Isabel. . Temporal Dynamics and Neuronal Specificity of Grin3a Expression in the Mouse Forebrain. In Cerebral cortex (New York, N.Y. : 1991), 31, 1914-1926. doi:10.1093/cercor/bhaa330. https://pubmed.ncbi.nlm.nih.gov/33290502/

5. Lin, Ying-Ju, Chang, Jeng-Sheng, Liu, Xiang, Chang, Li-Ching, Tsai, Fuu-Jen. 2013. Association between GRIN3A gene polymorphism in Kawasaki disease and coronary artery aneurysms in Taiwanese children. In PloS one, 8, e81384. doi:10.1371/journal.pone.0081384. https://pubmed.ncbi.nlm.nih.gov/24278430/