RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)

BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about the...

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Autores: Soto, D, Olivella, M, Grau, C, Armstrong, J, Alcon, C, Gasull, X, de Salazar, MG, Gratacos-Batlle, E, Ramos-Vicente, D, Fernandez-Duenas, V, Ciruela, F, Bayes, A, Sindreu, C, Lopez-Sala, A, Garcia-Cazorla, A, Altafaj, X
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p3978
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3978
Access Level:acceso abierto
Palabra clave:De novo mutation
D-serine
Glutamatergic neurotransmission
Neuropsychiatric disorders
NMDA receptor
Severe encephalopathy
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spelling RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)Soto, DOlivella, MGrau, CArmstrong, JAlcon, CGasull, Xde Salazar, MGGratacos-Batlle, ERamos-Vicente, DFernandez-Duenas, VCiruela, FBayes, ASindreu, CLopez-Sala, AGarcia-Cazorla, AAltafaj, XDe novo mutationD-serineGlutamatergic neurotransmissionNeuropsychiatric disordersNMDA receptorSevere encephalopathyBACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p. P553T) coding for the GluN2B subunit of NMDAR. METHODS: We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. RESULTS: Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p. P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. CONCLUSIONS: Our data suggest that hypofunctional NMDARs containing GluN2B( p. P553T) can contribute to Rettlike encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.ELSEVIER SCIENCE INC2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3978BIOLOGICAL PSYCHIATRYISSN: 00063223ISSNe: 18732402reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p39782026-06-14T12:41:47Z
dc.title.none.fl_str_mv RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
title RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
spellingShingle RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
Soto, D
De novo mutation
D-serine
Glutamatergic neurotransmission
Neuropsychiatric disorders
NMDA receptor
Severe encephalopathy
title_short RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
title_full RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
title_fullStr RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
title_full_unstemmed RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
title_sort RETRACTED: Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article. See vol. 83, pg. 715, 2018)
dc.creator.none.fl_str_mv Soto, D
Olivella, M
Grau, C
Armstrong, J
Alcon, C
Gasull, X
de Salazar, MG
Gratacos-Batlle, E
Ramos-Vicente, D
Fernandez-Duenas, V
Ciruela, F
Bayes, A
Sindreu, C
Lopez-Sala, A
Garcia-Cazorla, A
Altafaj, X
author Soto, D
author_facet Soto, D
Olivella, M
Grau, C
Armstrong, J
Alcon, C
Gasull, X
de Salazar, MG
Gratacos-Batlle, E
Ramos-Vicente, D
Fernandez-Duenas, V
Ciruela, F
Bayes, A
Sindreu, C
Lopez-Sala, A
Garcia-Cazorla, A
Altafaj, X
author_role author
author2 Olivella, M
Grau, C
Armstrong, J
Alcon, C
Gasull, X
de Salazar, MG
Gratacos-Batlle, E
Ramos-Vicente, D
Fernandez-Duenas, V
Ciruela, F
Bayes, A
Sindreu, C
Lopez-Sala, A
Garcia-Cazorla, A
Altafaj, X
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv De novo mutation
D-serine
Glutamatergic neurotransmission
Neuropsychiatric disorders
NMDA receptor
Severe encephalopathy
topic De novo mutation
D-serine
Glutamatergic neurotransmission
Neuropsychiatric disorders
NMDA receptor
Severe encephalopathy
description BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p. P553T) coding for the GluN2B subunit of NMDAR. METHODS: We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. RESULTS: Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p. P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. CONCLUSIONS: Our data suggest that hypofunctional NMDARs containing GluN2B( p. P553T) can contribute to Rettlike encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement.
publishDate 2018
dc.date.none.fl_str_mv 2018
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://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3978
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3978
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ELSEVIER SCIENCE INC
publisher.none.fl_str_mv ELSEVIER SCIENCE INC
dc.source.none.fl_str_mv BIOLOGICAL PSYCHIATRY
ISSN: 00063223
ISSNe: 18732402
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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repository.mail.fl_str_mv
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