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

XiangWei, Wenshu, Perszyk, Riley E., Liu, Nana, Xu, Yuchen, Bhattacharya, Subhrajit, Shaulsky, Gil H., Smith-Hicks, Constance, Fatemi, Ali, Fry, Andrew E. ORCID: https://orcid.org/0000-0001-9778-6924, 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 and Traynelis, Stephen F. 2023. Clinical and functional consequences of GRIA variants in patients with neurological diseases. Cellular and Molecular Life Sciences 80 (11) , 345. 10.1007/s00018-023-04991-6

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Abstract

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 EC50, 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer
ISSN:	1420-682X
Date of First Compliant Deposit:	22 November 2024
Date of Acceptance:	28 September 2023
Last Modified:	27 Jan 2025 14:30
URI:	https://orca.cardiff.ac.uk/id/eprint/174229

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