%0 Journal Article
%A Santos-Gomez, Ana
%A Miguez-Cabello, Federico
%A Julia-Palacios, Natalia
%A Garcia-Navas, Deyanira
%A Soto-Insuga, Victor
%A Garcia-Penas, Juan J.
%A Fuentes, Patricia
%A Ibanez-Mico, Salvador
%A Cuesta, Laura
%A Cancho, Ramon
%A Andreo-Lillo, Patricia
%A Gutierrez-Aguilar, Gema
%A Alonso-Luengo, Olga
%A Malaga, Ignacio
%A Hedrera-Fernandez, Antonio
%A Garcia-Cazorla, Angels
%A Soto, David
%A Olivella, Mireia
%A Altafaj, Xavier
%T Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
%D 2021
%U https://hdl.handle.net/10668/25066
%X 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 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.
%K GRIN-related disorders
%K glutamatergic neurotransmission
%K NMDA receptors
%K neurodevelopmental disorders
%K Synaptic plasticity
%K Nmda
%K Mutations
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