Santos Gómez, AnaMiguez Cabello, FedericoJuliá Palacios, NataliaGarcía Navas, DeyaniraSoto Insuga, VíctorGarcía Peñas, Juan J.Fuentes, PatriciaIbáñez Micó, SalvadorCuesta, LauraCancho, RamónAndreo Lillo, PatriciaGutiérrez Aguilar, GemaAlonso Luengo, OlgaMálaga, IgnacioHedrera Fernández, AntonioGarcía Cazorla, ÀngelsSoto del Cerro, DavidOlivella, MireiaAltafaj, Xavier2022-02-232022-02-232021-11-231661-6596https://hdl.handle.net/2445/183474Background: 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 deeplyphenotyped. 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 genotypephenotype association, contributing to future precision medicine of GRIN1-related encephalop19 p.application/pdfengcc-by (c) Santos Gómez, Ana et al., 2021https://creativecommons.org/licenses/by/4.0/NeurotransmissióNeurobiologia del desenvolupamentNeural transmissionDevelopmental neurobiologyinfo:eu-repo/semantics/article7180202022-02-23info:eu-repo/semantics/openAccess