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oai:uvadoc.uva.es:10324/647112025-02-28T13:18:56Zcom_10324_1181com_10324_931com_10324_894col_10324_1387

Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum Santos Gómez, Ana Míguez Cabello, Federico Juliá Palacios, Natalia García Navas, Deyanira Soto Insuga, Víctor García Peñas, Juan J. Fuentes, Patricia Ibáñez Micó, Salvador Cuesta, Laura Cancho Candela, Ramón Andreo Lillo, Patricia Gutiérrez Aguilar, Gema Alonso Luengo, Olga Málaga, Ignacio Hedrera Fernández, Antonio García Cazorla, Àngels Soto, David Olivella, Mireia Altafaj, Xavier Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although in termediate complex scenarios are often present. Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. Con clusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype phenotype association, contributing to future precision medicine of GRIN1-related encephalopathi 2024-01-18T07:50:41Z 2024-01-18T07:50:41Z 2021 info:eu-repo/semantics/article International Journal of Molecular Sciences 2021; 22(23):12656 https://uvadoc.uva.es/handle/10324/64711 10.3390/ijms222312656 spa info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/ Attribution-NonCommercial-NoDerivatives 4.0 Internacional MDPI SI