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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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 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.

Details

Title
Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
Author
Santos-Gómez, Ana 1 ; Miguez-Cabello, Federico 1 ; Juliá-Palacios, Natalia 2 ; García-Navas, Deyanira 3 ; Soto-Insuga, Víctor 4 ; García-Peñas, Juan J 4 ; Fuentes, Patricia 5 ; Ibáñez-Micó, Salvador 6   VIAFID ORCID Logo  ; Cuesta, Laura 7 ; Cancho, Ramón 8 ; Andreo-Lillo, Patricia 9 ; Gutiérrez-Aguilar, Gema 10 ; Alonso-Luengo, Olga 11 ; Málaga, Ignacio 12   VIAFID ORCID Logo  ; Hedrera-Fernández, Antonio 12 ; García-Cazorla, Àngels 2 ; Soto, David 1 ; Olivella, Mireia 13 ; Altafaj, Xavier 1 

 Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain; [email protected] (A.S.-G.); [email protected] (F.M.-C.); [email protected] (D.S.); August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain 
 Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu—CIBERER, 08950 Barcelona, Spain; [email protected] (N.J.-P.); [email protected] (À.G.-C.) 
 Department of Pediatric Neurology, Hospital Universitario San Pedro de Alcántara, 10001 Cáceres, Spain; [email protected] 
 Neurology Service, Hospital Niño Jesús, 28009 Madrid, Spain; [email protected] (V.S.-I.); [email protected] (J.J.G.-P.) 
 Neuropediatrics Unit, Hospital Clínico Santiago de Compostela, 15706 Santiago de Compostela, Spain; [email protected] 
 Pediatric Neurology Unit, Arrixaca Universitary Hospital, 30120 Murcia, Spain; [email protected] 
 Department of Paediatrics Neurology, Hospital de Manises, 46940 Valencia, Spain; [email protected] 
 Pediatric Neurology, Department of Pediatrics, Hospital Universitario Río Hortega, 47012 Valladolid, Spain; [email protected] 
 Neuropediatric Unit, Pediatric Department, University Hospital of Sant Joan d’Alacant, 03550 Sant Joan d’Alacant, Spain; [email protected] 
10  Pediatrics Unit, Hospital Universitario de Jerez de la Frontera, 11407 Jerez de la Frontera, Spain; [email protected] 
11  Department of Pediatrics, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain; [email protected] 
12  Child Neurology Unit, Pediatrics Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; [email protected] (I.M.); [email protected] (A.H.-F.) 
13  Bioinfomatics and Medical Statistics Group, University of Vic—Central University of Catalonia, 08500 Vic, Spain 
First page
12656
Publication year
2021
Publication date
2021
Publisher
MDPI AG
ISSN
16616596
e-ISSN
14220067
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2608119131
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.