RT info:eu-repo/semantics/article
T1 Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
A1 Santos Gómez, Ana
A1 Míguez Cabello, Federico
A1 Juliá Palacios, Natalia
A1 García Navas, Deyanira
A1 Soto Insuga, Víctor
A1 García Peñas, Juan J.
A1 Fuentes, Patricia
A1 Ibáñez Micó, Salvador
A1 Cuesta, Laura
A1 Cancho Candela, Ramón
A1 Andreo Lillo, Patricia
A1 Gutiérrez Aguilar, Gema
A1 Alonso Luengo, Olga
A1 Málaga, Ignacio
A1 Hedrera Fernández, Antonio
A1 García Cazorla, Àngels
A1 Soto, David
A1 Olivella, Mireia
A1 Altafaj, Xavier
AB Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rareencephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2Bgenes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropicglutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1subunit 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 thestructural and functional alterations of GRIN1 disease-associated variants, and their correlations withclinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring thesevariants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply phenotyped. Further, using computational and in vitro approaches, we identified different criticalcheckpoints 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 andfunctional outcomes. This structural-functional stratification provides relevant insights of genotype phenotype association, contributing to future precision medicine of GRIN1-related encephalopathi
PB MDPI
YR 2021
FD 2021
LK https://uvadoc.uva.es/handle/10324/64711
UL https://uvadoc.uva.es/handle/10324/64711
LA spa
NO International Journal of Molecular Sciences 2021; 22(23):12656
DS UVaDOC
RD 04-abr-2025