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

Wenshu XiangWei, Varun Kannan, Yuchen Xu, Gabrielle J Kosobucki, Anthony J Schulien, Hirofumi Kusumoto, Christelle Moufawad El Achkar, Subhrajit Bhattacharya, Gaetan Lesca, Sylvie Nguyen, Katherine L Helbig, Jean-Marie Cuisset, Christina Dühring Fenger, Dragan Marjanovic, Elisabeth Schuler, Ye Wu, Xinhua Bao, Yuehua Zhang, Nina Dirkx, An-Sofie SchoonjansSteffen Syrbe, Scott J Myers, Annapurna Poduri, Elias Aizenman, Stephen F Traynelis, Johannes R Lemke, Hongjie Yuan, Yuwu Jiang

Publikation: Bidrag til tidsskriftArtikelForskningpeer review

Abstrakt

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.

OriginalsprogEngelsk
Sider (fra-til)3009-3027
Antal sider19
TidsskriftBrain
Vol/bind142
Udgave nummer10
DOI
StatusUdgivet - 1 okt. 2019

Bibliografisk note

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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