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Among AMPAR subunits, GluA2 is unique because of its role in forming Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010impermeable heteromeric receptors with GluA1\/A3\/A4, a property dictated by an arginine residue (GluA2(R)) in the pore region. In contrast, GluA2(R)\u2010lacking AMPARs are Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010permeable. Through whole\u2010exome sequencing (WES), we identified a de novo\n                    <jats:italic>GRIA2<\/jats:italic>\n                    variant (c.1945A&gt;T, p.Arg649Trp) in a patient with neurodevelopmental disorders (NDDs) and epilepsy. Heterologous expression in HEK293T cells revealed that homomeric GluA2(Q)_Arg649Trp and heteromeric GluA1\/A2(R)_Arg649Trp receptors retained near\u2010normal gating kinetics compared to wild\u2010type (WT). However, rectification index (RI) analysis demonstrated impaired assembly of GluA2(R)_Arg649Trp with GluA1. At 1:1 or 1:2 expression ratio (GluA1:GluA2), the Arg649Trp mutant exhibited a lower RI than WT, accompanied by reduced surface expression when coexpressed with GluA1. These results suggest that the Arg649Trp variant compromises the ability of GluA2 to incorporate into heteromeric AMPARs, leading to an increased proportion of GluA1 homomeric\/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010permeable receptors. Notably, recurrent missense variants at the M3\u2013S2 linker of GluA2, including Ala639Ser and Thr646Asn, have also been independently identified to impair AMPAR assembly, suggesting this could be a common pathological mechanism. We thus propose that altered subunit stoichiometry, rather than changes in channel gating kinetics, represents a primary pathogenic mechanism for this\n                    <jats:italic>GRIA2<\/jats:italic>\n                    variant, contributing to NDD pathogenesis by elevating Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010permeable AMPARs in the brain.\n                  <\/jats:p>","DOI":"10.1155\/humu\/3227151","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:25:19Z","timestamp":1790850319000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A De Novo Arg649Trp Variant in GluA2 Impairs Its Assembly With GluA1: Associated With Epilepsy and Neurodevelopmental Disorders"],"prefix":"10.1155","volume":"2026","author":[{"given":"Jing-Wen","family":"Chen","sequence":"first","affiliation":[{"name":"Ministry of Education Key Laboratory of Model 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