Journal article
Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology
KK Ogden, W Chen, SA Swanger, MJ McDaniel, LZ Fan, C Hu, A Tankovic, H Kusumoto, GJ Kosobucki, AJ Schulien, Z Su, J Pecha, S Bhattacharya, S Petrovski, AE Cohen, E Aizenman, SF Traynelis, H Yuan
Plos Genetics | PUBLIC LIBRARY SCIENCE | Published : 2017
Open access
Abstract
N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay. We find mutant GluN1/GluN2A recept..
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Awarded by National Institute of Child Health and Human Development
Funding Acknowledgements
This work was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under award number R01HD082373 to HY, by the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH under award number R01NS036654 to SFT, award number R24NS092989 to SFT,and award number R01NS043277 to EA, by the Xiangya Emory Medical Schools Visiting Student Program toWC, by Emory+Children's Pediatric Center Seed Grant Program to HY, and by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 to HY. LZF and AEC are supported by the Howard Hughes Medical Institute. SP is supported by the National Health and Medical Research Council of Australia. The funders had no rolein study design, data collection and analysis, decision to publish, or preparation of the manuscript.