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Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article.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)
Por:
Soto D, Olivella M, Grau C, Armstrong-Moron J, Alcon C, Gasull X, Gómez de Salazar M, Gratacòs-Batlle E, Ramos-Vicente D, Fernández-Dueñas V, Ciruela F, Bayés À, Sindreu C, López-Sala A, Garcia-Cazorla A and Altafaj X
Publicada:
15 ene 2018
Ahead of Print:
16 jun 2017
Categoría:
Biological psychiatry
Resumen:
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.
Filiaciones:
Soto D:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Biomedicine, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
Olivella M:
Bioinfomatics and Medical Statistics Group, University of Vic-Central University of Catalonia, Barcelona, Spain
Grau C:
Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain
Armstrong-Moron J:
Genetics and Molecular Medicine Service, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Molecular Physiology of the Synapse Laboratory, Barcelona, Spain
Alcon C:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Clinical Foundations, University of Barcelona, Barcelona, Spain
Gasull X:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Biomedicine, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
Gómez de Salazar M:
Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain
Gratacòs-Batlle E:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Biomedicine, University of Barcelona, Barcelona, Spain
August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
Ramos-Vicente D:
Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau, Barcelona, Spain
Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
Fernández-Dueñas V:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain
Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain
Ciruela F:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain
Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain
Bayés À:
Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau, Barcelona, Spain
Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
Sindreu C:
Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Department of Clinical Foundations, University of Barcelona, Barcelona, Spain
López-Sala A:
Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Molecular Physiology of the Synapse Laboratory, Barcelona, Spain
Garcia-Cazorla A:
Genetics and Molecular Medicine Service, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Molecular Physiology of the Synapse Laboratory, Barcelona, Spain
Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and Centro de Investigación Biomédica en Red de Enfermedades Raras, Molecular Physiology of the Synapse Laboratory, Barcelona, Spain
Altafaj X:
Bellvitge Biomedical Research Institute-Unit of Neuropharmacology and Pain Group, University of Barcelona, Barcelona, Spain
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