RT Journal Article
T1 Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
A1 Santos-Gomez, Ana
A1 Miguez-Cabello, Federico
A1 Julia-Palacios, Natalia
A1 Garcia-Navas, Deyanira
A1 Soto-Insuga, Victor
A1 Garcia-Penas, Juan J.
A1 Fuentes, Patricia
A1 Ibanez-Mico, Salvador
A1 Cuesta, Laura
A1 Cancho, Ramon
A1 Andreo-Lillo, Patricia
A1 Gutierrez-Aguilar, Gema
A1 Alonso-Luengo, Olga
A1 Malaga, Ignacio
A1 Hedrera-Fernandez, Antonio
A1 Garcia-Cazorla, Angels
A1 Soto, David
A1 Olivella, Mireia
A1 Altafaj, Xavier
K1 GRIN-related disorders
K1 glutamatergic neurotransmission
K1 NMDA receptors
K1 neurodevelopmental disorders
K1 Synaptic plasticity
K1 Nmda
K1 Mutations
AB 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.
PB Mdpi
YR 2021
FD 2021-12-01
LK https://hdl.handle.net/10668/25066
UL https://hdl.handle.net/10668/25066
LA en
DS RISalud
RD Apr 6, 2025