Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
Por:
Santos-Gómez A, Miguez-Cabello F, Julià-Palacios NA, García-Navas D, Soto-Insuga V, García-Peñas JJ, Fuentes P, Ibáñez-Micó S, Cuesta L, Cancho R, Andreo-Lillo P, Gutiérrez-Aguilar G, Alonso-Luengo O, Málaga I, Hedrera-Fernández A, Garcia-Cazorla A, Soto D, Olivella M and Altafaj X
Publicada:
1 dic 2021
Ahead of Print:
23 nov 2021
Resumen:
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.
Filiaciones:
Santos-Gómez A:
Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain
Miguez-Cabello F:
Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain
Julià-Palacios NA:
Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu-CIBERER, 08950 Barcelona, Spain
García-Navas D:
Department of Pediatric Neurology, Hospital Universitario San Pedro de Alcántara, 10001 Cáceres, Spain
Soto-Insuga V:
Neurology Service, Hospital Niño Jesús, 28009 Madrid, Spain
García-Peñas JJ:
Neurology Service, Hospital Niño Jesús, 28009 Madrid, Spain
Fuentes P:
Neuropediatrics Unit, Hospital Clínico Santiago de Compostela, 15706 Santiago de Compostela, Spain
Ibáñez-Micó S:
Pediatric Neurology Unit, Arrixaca Universitary Hospital, 30120 Murcia, Spain
Cuesta L:
Department of Paediatrics Neurology, Hospital de Manises, 46940 Valencia, Spain
Cancho R:
Pediatric Neurology, Department of Pediatrics, Hospital Universitario Río Hortega, 47012 Valladolid, Spain
Andreo-Lillo P:
Neuropediatric Unit, Pediatric Department, University Hospital of Sant Joan d'Alacant, 03550 Sant Joan d'Alacant, Spain
Gutiérrez-Aguilar G:
Pediatrics Unit, Hospital Universitario de Jerez de la Frontera, 11407 Jerez de la Frontera, Spain
Alonso-Luengo O:
Department of Pediatrics, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain
Málaga I:
Child Neurology Unit, Pediatrics Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
Hedrera-Fernández A:
Child Neurology Unit, Pediatrics Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
Garcia-Cazorla A:
Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu-CIBERER, 08950 Barcelona, Spain
Soto D:
Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain
Olivella M:
Bioinfomatics and Medical Statistics Group, University of Vic-Central University of Catalonia, 08500 Vic, Spain
Altafaj X:
Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain
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