Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum
Por:
Santos-Gomez, A, Miguez-Cabello, F, Julia-Palacios, N, Garcia-Navas, D, Soto-Insuga, V, Garcia-Penas, J, Fuentes, P, Ibanez-Mico, S, Cuesta, L, Cancho, R, Andreo-Lillo, P, Gutierrez-Aguilar, G, Alonso-Luengo, O, Malaga, I, Hedrera-Fernandez, A, Garcia-Cazorla, A, Soto, D, Olivella, M and Altafaj, X
Publicada:
1 dic 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-Gomez, A:
Univ Barcelona, Neurophysiol Lab, Dept Biomed, Fac Med & Hlth Sci,Inst Neurosci, Barcelona 08036, Spain
Univ Barcelona, August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Miguez-Cabello, F:
Univ Barcelona, Neurophysiol Lab, Dept Biomed, Fac Med & Hlth Sci,Inst Neurosci, Barcelona 08036, Spain
Univ Barcelona, August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Julia-Palacios, N:
Hosp St Joan de Deu CIBERER, Dept Neurol, Neurometab Unit, Barcelona 08950, Spain
Garcia-Navas, D:
Hosp Univ San Pedro de Alcantara, Dept Pediat Neurol, Caceres 10001, Spain
Soto-Insuga, V:
Hosp Nino Jesus, Neurol Serv, Madrid 28009, Spain
Garcia-Penas, J:
Hosp Nino Jesus, Neurol Serv, Madrid 28009, Spain
Fuentes, P:
Hosp Clin Santiago de Compostela, Neuropediat Unit, Santiago De Compostela 15706, Spain
Ibanez-Mico, S:
Arrixaca Univ Hosp, Pediat Neurol Unit, Murcia 30120, Spain
Cuesta, L:
Hosp Manises, Dept Paediat Neurol, Valencia 46940, Spain
Cancho, R:
Hosp Univ Rio Hortega, Dept Pediat, Pediat Neurol, Valladolid 47012, Spain
:
Univ Hosp St Joan dAlacant, Dept Pediat, Neuropediat Unit, Sant Joan dAlacant 03550, Spain
Gutierrez-Aguilar, G:
Hosp Univ Jerez de la Frontera, Pediat Unit, Jerez de la Frontera 11407, Spain
Alonso-Luengo, O:
Hosp Univ Virgen del Rocio, Dept Pediat, Seville 41013, Spain
Malaga, I:
Hosp Univ Cent Asturias, Dept Pediat, Child Neurol Unit, Oviedo 33011, Spain
Hedrera-Fernandez, A:
Hosp Univ Cent Asturias, Dept Pediat, Child Neurol Unit, Oviedo 33011, Spain
Garcia-Cazorla, A:
Hosp St Joan de Deu CIBERER, Dept Neurol, Neurometab Unit, Barcelona 08950, Spain
Soto, D:
Univ Barcelona, Neurophysiol Lab, Dept Biomed, Fac Med & Hlth Sci,Inst Neurosci, Barcelona 08036, Spain
Univ Barcelona, August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Olivella, M:
Univ Vic Cent Univ Catalonia, Bioinfomat & Med Stat Grp, Vic 08500, Spain
Altafaj, X:
Univ Barcelona, Neurophysiol Lab, Dept Biomed, Fac Med & Hlth Sci,Inst Neurosci, Barcelona 08036, Spain
Univ Barcelona, August Pi & Sunyer Biomed Res Inst IDIBAPS, Barcelona 08036, Spain
Green Published, gold
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