De Novo GRIN Variants in NMDA Receptor M2 Channel Pore-Forming Loop Are Associated with Neurological Diseases.

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ID: 12315
2019
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Abstract
N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, GRIN2B that alter residues in the M2 reentrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge transfer in addition to varied and complex influences on NMDAR functional properties, which may underlie the patients' phenotypes. This article is protected by copyright. All rights reserved.
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li2019dehuman Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Li, Jia;Zhang, Jin;Tang, Weiting;Mizu, Ruth K;Kusumoto, Hirofumi;XiangWei, Wenshu;Xu, Yuchen;Chen, Wenjuan;Amin, Johansen B;Perozo, Eduardo;Hu, Chun;Kannan, Varun;Keller, Stephanie R;Wilcox, William R;Lemke, Johannes R;Myers, Scott J;Swanger, Sharon A;Wollmuth, Lonnie P;Petrovski, Slavé;Traynelis, Stephen F;Yuan, Hongjie;
Journal human mutation
Year 2019
DOI
10.1002/humu.23895
URL
Keywords Keywords not found

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