Clinical and functional consequences of GRIA variants in patients with neurological diseases

• Published in: Cellular and molecular life sciences : CMLS 2023-11, Vol.80 (11), p.345-345, Article 345
• Main Authors: XiangWei, Wenshu, Perszyk, Riley E., Liu, Nana, Xu, Yuchen, Bhattacharya, Subhrajit, Shaulsky, Gil H., Smith-Hicks, Constance, Fatemi, Ali, Fry, Andrew E., Chandler, Kate, Wang, Tao, Vogt, Julie, Cohen, Julie S., Paciorkowski, Alex R., Poduri, Annapurna, Zhang, Yuehua, Wang, Shuang, Wang, Yuping, Zhai, Qiongxiang, Fang, Fang, Leng, Jie, Garber, Kathryn, Myers, Scott J., Jauss, Robin-Tobias, Park, Kristen L., Benke, Timothy A., Lemke, Johannes R., Yuan, Hongjie, Jiang, Yuwu, Traynelis, Stephen F.
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Circuits; Convulsions & seizures; Desensitization; Epilepsy; Genes; Genetic diversity; Glutamate receptors; Hospitals; Humans; Life Sciences; Localization; Modulators; Nervous System Diseases - genetics; Neurological diseases; Neuromodulation; Original; Original Article; Ovaries; Patients; Phenotypes; Receptors; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Sensitivity analysis; Synapses; Synapses - metabolism; Synaptic transmission; Synaptic Transmission - physiology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-023-04991-6

AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1–4 identified in patients with various neurological disorders. These variants produce changes in agonist EC 50 , response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients’ clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.