RT info:eu-repo/semantics/article
T1 Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
A1 Cancho, Ramon
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 25-nov-2024