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

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

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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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

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spelling	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical SpectrumSantos Gómez, AnaMíguez Cabello, FedericoJuliá Palacios, NataliaGarcía Navas, DeyaniraSoto Insuga, VíctorGarcía Peñas, Juan J.Fuentes, PatriciaIbáñez Micó, SalvadorCuesta, LauraCancho Candela, RamónAndreo Lillo, PatriciaGutiérrez Aguilar, GemaAlonso Luengo, OlgaMálaga, IgnacioHedrera Fernández, AntonioGarcía Cazorla, ÀngelsSoto, DavidOlivella, MireiaAltafaj, XavierBackground: 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 encephalopathiInternational Journal of Molecular Sciences 2021; 22(23):12656MDPI2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://doi.org/10.3390/ijms222312656https://uvadoc.uva.es/handle/10324/64711reponame:UVaDOC. Repositorio Documental de la Universidad de Valladolidinstname:Universidad de ValladolidEspañolinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:uvadoc.uva.es:10324/647112026-06-13T12:44:47Z
dc.title.none.fl_str_mv	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
title	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
spellingShingle	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum Santos Gómez, Ana
title_short	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
title_full	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
title_fullStr	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
title_full_unstemmed	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
title_sort	Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
dc.creator.none.fl_str_mv	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
author	Santos Gómez, Ana
author_facet	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
author_role	author
author2	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
author2_role	author author author author author author author author author author author author author author author author author author
description	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
publishDate	2021
dc.date.none.fl_str_mv	2021
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://doi.org/10.3390/ijms222312656 https://uvadoc.uva.es/handle/10324/64711
url	https://doi.org/10.3390/ijms222312656 https://uvadoc.uva.es/handle/10324/64711
dc.language.none.fl_str_mv	Español
language_invalid_str_mv	Español
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
rights_invalid_str_mv	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	MDPI
publisher.none.fl_str_mv	MDPI
dc.source.none.fl_str_mv	reponame:UVaDOC. Repositorio Documental de la Universidad de Valladolid instname:Universidad de Valladolid
instname_str	Universidad de Valladolid
reponame_str	UVaDOC. Repositorio Documental de la Universidad de Valladolid
collection	UVaDOC. Repositorio Documental de la Universidad de Valladolid
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum

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