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Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement (Retracted article.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, 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
Publicada:
15 ene 2018
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:
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Univ Barcelona, Dept Biomed, Barcelona, Spain
Univ Vic Cent Univ Catalonia, August Pi & Sunyer Biomed Res Inst, Barcelona, Spain
Olivella, M:
Univ Vic Cent Univ Catalonia, Bioinfomat & Med Stat Grp, Barcelona, Spain
Grau, C:
Univ Barcelona, Bellvitge Biomed Res Inst, Unit Neuropharmacol, Barcelona, Spain
Univ Barcelona, Pain Grp, Barcelona, Spain
Armstrong, J:
Hosp St Joan de Deu, Genet & Mol Med Serv, Barcelona, Spain
Alcon, C:
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Univ Barcelona, Dept Clin Foundat, Barcelona, Spain
Gasull, X:
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Univ Barcelona, Dept Biomed, Barcelona, Spain
Univ Vic Cent Univ Catalonia, August Pi & Sunyer Biomed Res Inst, Barcelona, Spain
de Salazar, MG:
Univ Barcelona, Bellvitge Biomed Res Inst, Unit Neuropharmacol, Barcelona, Spain
Univ Barcelona, Pain Grp, Barcelona, Spain
Gratacos-Batlle, E:
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Univ Barcelona, Dept Biomed, Barcelona, Spain
Univ Vic Cent Univ Catalonia, August Pi & Sunyer Biomed Res Inst, Barcelona, Spain
Ramos-Vicente, D:
Biomed Res Inst St Pau, Mol Physiol Synapse Lab, Ctr Invest Biomed Red Enfermedades Rara, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Fernandez-Duenas, V:
Univ Barcelona, Dept Pathol & Expt Therapeut, Barcelona, Spain
Univ Barcelona, Bellvitge Biomed Res Inst, Unit Neuropharmacol, Barcelona, Spain
Univ Barcelona, Pain Grp, Barcelona, Spain
Ciruela, F:
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Univ Barcelona, Dept Pathol & Expt Therapeut, Barcelona, Spain
Univ Barcelona, Bellvitge Biomed Res Inst, Unit Neuropharmacol, Barcelona, Spain
Univ Barcelona, Pain Grp, Barcelona, Spain
Bayes, A:
Biomed Res Inst St Pau, Mol Physiol Synapse Lab, Ctr Invest Biomed Red Enfermedades Rara, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Sindreu, C:
Univ Barcelona, Inst Neurosci, Barcelona, Spain
Univ Barcelona, Dept Clin Foundat, Barcelona, Spain
Lopez-Sala, A:
Hosp St Joan de Deu, Dept Neurol, Neurometab Unit, Barcelona, Spain
Garcia-Cazorla, A:
Hosp St Joan de Deu, Genet & Mol Med Serv, Barcelona, Spain
Hosp St Joan de Deu, Dept Neurol, Neurometab Unit, Barcelona, Spain
Altafaj, X:
Univ Barcelona, Bellvitge Biomed Res Inst, Unit Neuropharmacol, Barcelona, Spain
Univ Barcelona, Pain Grp, Barcelona, Spain
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