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Brain. 2019 Oct 1;142(10):3009-3027. doi: 10.1093/brain/awz232.

Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.

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Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Neurobiology, University of Pittsburgh School of Medicine and Pittsburgh Institute for Neurodegenerative Diseases, Pittsburgh PA, USA.
Division of Epilepsy, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
Department of Neurology, Harvard Medical School, Boston, MA, USA.
Service de Genetique, Centre de Reference Anomalies du Developpement, Hospices Civils de Lyon, Bron, France; INSERM U1028, CNRS UMR5292, Paris, France.
Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Universite Claude Bernard Lyon 1, Bron, France; Claude Bernard Lyon I University, Lyon, France.
Department of Pediatric Neurology, University Hospital of Lille, and Lille Reference Centre for Rare Epileptic Disorders, Lille, France.
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Neurogenetics Group, University of Antwerp, Belgium.
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Department of Child Neurology, Antwerp University Hospital, Antwerp, Belgium.
Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.


N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.


GluN; NMDA receptor; channelopathy; functional genomics; glutamate receptor

[Available on 2020-10-01]

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