Santos-Gomez, AnaMiguez-Cabello, FedericoJulia-Palacios, NataliaGarcia-Navas, DeyaniraSoto-Insuga, VictorGarcia-Penas, Juan J.Fuentes, PatriciaIbanez-Mico, SalvadorCuesta, LauraCancho, RamonAndreo-Lillo, PatriciaGutierrez-Aguilar, GemaAlonso-Luengo, OlgaMalaga, IgnacioHedrera-Fernandez, AntonioGarcia-Cazorla, AngelsSoto, DavidOlivella, MireiaAltafaj, Xavier2025-01-072025-01-072021-12-01https://hdl.handle.net/10668/25066Background: 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 intermediate 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. Conclusions: 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 encephalopathies.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/GRIN-related disordersglutamatergic neurotransmissionNMDA receptorsneurodevelopmental disordersSynaptic plasticityNmdaMutationsresearch article34884460open access10.3390/ijms2223126561422-0067https://www.mdpi.com/1422-0067/22/23/12656/pdf?version=1637821610735015600001