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...

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Detalles Bibliográficos
Autores: Santos Gómez, Ana, Miguez Cabello, Federico, Juliá Palacios, Natalia, García Navas, Deyanira, Soto Insuga, Víctor, García Peñas, Juan J., Fuentes, Patricia, Ibáñez Micó, Salvador, Cuesta, Laura, Cancho, Ramón, Andreo Lillo, Patricia, Gutiérrez Aguilar, Gema, Alonso Luengo, Olga, Málaga, Ignacio, Hedrera Fernández, Antonio, García Cazorla, Àngels, Soto del Cerro, David, Olivella, Mireia, Altafaj, Xavier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/183474
Acceso en línea:https://hdl.handle.net/2445/183474
Access Level:acceso abierto
Palabra clave:Neurotransmissió
Neurobiologia del desenvolupament
Neural transmission
Developmental neurobiology
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 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 deeplyphenotyped. 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 genotypephenotype association, contributing to future precision medicine of GRIN1-related encephalop

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