Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy
| Autor: | Subhrajit Bhattacharya, Varun Kannan, Hirofumi Kusumoto, Yuehua Zhang, Gabrielle J. Kosobucki, An-Sofie Schoonjans, Annapurna Poduri, Sylvie Nguyen, Xinhua Bao, Elias Aizenman, Elisabeth Schuler, Dragan Marjanovic, Hongjie Yuan, Scott J. Myers, Christelle Moufawad El Achkar, Christina Fenger, Nina Dirkx, Gaetan Lesca, Yuwu Jiang, Stephen F. Traynelis, Jean-Marie Cuisset, Ye Wu, Wenshu XiangWei, Steffen Syrbe, Katherine L. Helbig, Anthony J. Schulien, Johannes R. Lemke, Yuchen Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist Adult Male medicine.drug_class Protein subunit Glutamic Acid Neurotransmission Polymorphism Single Nucleotide Receptors N-Methyl-D-Aspartate Synaptic Transmission Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Amino Acid Sequence Receptor Child Neurons Chemistry Glutamate receptor Original Articles Cell biology Rats Transmembrane domain 030104 developmental biology HEK293 Cells Gene Expression Regulation Child Preschool NMDA receptor Epilepsy Generalized Female Neurology (clinical) Human medicine 030217 neurology & neurosurgery Ionotropic effect |
| Zdroj: | Brain |
| ISSN: | 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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