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Title: | Paradigmatic de novo GRIN1 variants recapitulate pathophysiological mechanisms underlying GRIN1-related disorder clinical spectrum |
Author: | 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 |
Keywords: | Neurotransmissió Neurobiologia del desenvolupament Neural transmission Developmental neurobiology |
Issue Date: | 23-Nov-2021 |
Publisher: | MDPI |
Abstract: | 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 |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/ijms222312656 |
It is part of: | International Journal of Molecular Sciences, 2021, vol. 22, num. 23, p. 12656 |
URI: | http://hdl.handle.net/2445/183474 |
Related resource: | https://doi.org/10.3390/ijms222312656 |
ISSN: | 1661-6596 |
Appears in Collections: | Articles publicats en revistes (Institut de Neurociències (UBNeuro)) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Biomedicina) |
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