Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum

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 growi...

Descripción completa

Detalles Bibliográficos
Autores: Santos Gómez, Ana, Míguez Cabello, Federico, Juliá Palacios, Natalia, García Navas, Deyanira, Soto Insuga, Víctor, García Peñas, Juan J., Fuentes, Patricia, Ibáñez Micó, Salvador, Cuesta, Laura, Cancho Candela, Ramón, Andreo Lillo, Patricia, Gutiérrez Aguilar, Gema, Alonso Luengo, Olga, Málaga, Ignacio, Hedrera Fernández, Antonio, García Cazorla, Àngels, Soto, David, Olivella, Mireia, Altafaj, Xavier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Valladolid
Repositorio:UVaDOC. Repositorio Documental de la Universidad de Valladolid
OAI Identifier:oai:uvadoc.uva.es:10324/64711
Acceso en línea:https://doi.org/10.3390/ijms222312656
https://uvadoc.uva.es/handle/10324/64711
Access Level:acceso abierto
Descripción
Sumario: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 in termediate 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. Con clusions: 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 encephalopathi

Similares en LA Referencia