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Genetic variation in GRIN genes encoding N-methyl-D-aspartate receptor (NMDAR) subunits has been associated with a spectrum of neurological and neuropsychiatric disorders. This talk will focus on clinical phenotype, functional consequences, and potential rescue pharmacology of disease-associated GRIN2D missense variants. The GRIN2D variants are located in the pre-M1 helix, agonist-binding domain, transmembrane domain M3, and the intracellular CTD. Developmental and epileptic encephalopathy (DEE) is the unifying phenotype across all 13 patients. The seizure types ranged from focal seizures, atypical absence seizures, tonic or atonic seizures, to epileptic spasms. Eight patients showed certain degree of hypotonia and movement disorders, three patients have autistic behavior and one patient showed symptoms of ADHD. Functional analysis in vitro on six novel GRIN2D variants reveals that that all six variants decreased receptor surface expression, which may underline certain shared clinical symptoms. Three variants (Leu670Phe, Ala675Thr, Ala678Asp) showed significantly enhanced agonist potency, and/or increased channel open probability, while the other three (Ser573Phe, Ser1271Phe, Arg1313Trp) presented reduced
sensitivity to endogenous protons and decreased channel open probability. Three variants (Ser573Phe, Ala675Thr, Ala678Asp) significantly decrease current amplitude. GluN2D-Leu670Phe
prolongs synaptic-like response time course and increases charge transfer. GluN2D-Ala678Asp transfection significantly reduced cell viability of cultured cortical neurons. In addition, a set of FDA-approved NMDAR channel blockers were evaluated for their ability to rescue functional changes of mutant receptors. This work suggests the importance of functional and biochemical validation for each individual variant. Rescue pharmacology in vitro may provide potential benefit of precision
medicine for a subset of severe pediatric neurodevelopmental diseases.