Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/21625
Title: De Novo GRIN Variants in NMDA Receptor M2 Channel Pore-Forming Loop Are Associated with Neurological Diseases.
Austin 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
Affiliation: Division of Pediatric Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA
Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, 30322, USA
Division of Medical Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
Centre for Genomics Research, Discovery Sciences, Biopharmaceuticals R&D,, AstraZeneca, Cambridge, CB4 0WG, UK
Department of Medicine, the University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, 3050, Australia
Department of Neurobiology & Behavior, Stony Brook University School of Medicine, Stony Brook, NY, 11794, USA
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 2019
metadata.dc.date: 2019-08-20
Publication information: Human mutation 2019; 40(12): 2393-2413
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21625
DOI: 10.1002/humu.23895
ORCID: 0000-0002-8127-7145
0000-0002-1527-961X
PubMed URL: 31429998
Type: Journal Article
Subjects: GluN
autism
channelopathy
epilepsy
glutamate receptor
intellectual disability
missense variants
movement disorder
neurological diseases
translation study
transmembrane domain
Appears in Collections:Journal articles

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