A de novo GRIN1 Variant Associated With Myoclonus and Developmental Delay: From Molecular Mechanism to Rescue Pharmacology

Jin Zhang, Weiting Tang, Nidhi K. Bhatia, Yuchen Xu, Nabina Paudyal, Ding Liu, Sukhan Kim, Rui Song, Wenshu XiangWei, Gil Shaulsky, Scott J. Myers, William Dobyns, Vasanthi Jayaraman, Stephen F. Traynelis, Hongjie Yuan, Xiuhua Bozarth

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1 Scopus citations

Abstract

N-Methyl-D-aspartate receptors (NMDARs) are highly expressed in brain and play important roles in neurodevelopment and various neuropathologic conditions. Here, we describe a new phenotype in an individual associated with a novel de novo deleterious variant in GRIN1 (c.1595C>A, p.Pro532His). The clinical phenotype is characterized with developmental encephalopathy, striking stimulus-sensitive myoclonus, and frontal lobe and frontal white matter hypoplasia, with no apparent seizures detected. NMDARs that contained the P532H within the glycine-binding domain of GluN1 with either the GluN2A or GluN2B subunits were evaluated for changes in their pharmacological and biophysical properties, which surprisingly revealed only modest changes in glycine potency but a significant decrease in glutamate potency, an increase in sensitivity to endogenous zinc inhibition, a decrease in response to maximally effective concentrations of agonists, a shortened synaptic-like response time course, a decreased channel open probability, and a reduced receptor cell surface expression. Molecule dynamics simulations suggested that the variant can lead to additional interactions across the dimer interface in the agonist-binding domains, resulting in a more open GluN2 agonist-binding domain cleft, which was also confirmed by single-molecule fluorescence resonance energy transfer measurements. Based on the functional deficits identified, several positive modulators were evaluated to explore potential rescue pharmacology.

Original languageEnglish (US)
Article number694312
JournalFrontiers in Genetics
Volume12
DOIs
StatePublished - Aug 3 2021
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Jing Zhang, Nana Liu, and Phoung Le for technical support, and Sage Therapeutics Inc. for supplying the 24(S)-hydroxycholesterol. Funding. This work was supported by NIH?the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HY, grant R01HD082373), by the NIH?National Institute of Neurologic Disorders and Stroke (NINDS) (ST, grants R35NS111619), by Austin Purpose (ST), by Emory-Xiangya Exchange Program (YX and RS), by NIH?National Institute of General Medical Sciences (NIGMS) (VJ, grant R35GM122528), and by HAMBP Fellowship NIH grant (NP, T32GM008280). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Funding Information:
This work was supported by NIH—the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HY, grant R01HD082373), by the NIH—National Institute of Neurologic Disorders and Stroke (NINDS) (ST, grants R35NS111619), by Austin Purpose (ST), by Emory-Xiangya Exchange Program (YX and RS), by NIH—National Institute of General Medical Sciences (NIGMS) (VJ, grant R35GM122528), and by HAMBP Fellowship NIH grant (NP, T32GM008280). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Publisher Copyright:
© Copyright © 2021 Zhang, Tang, Bhatia, Xu, Paudyal, Liu, Kim, Song, XiangWei, Shaulsky, Myers, Dobyns, Jayaraman, Traynelis, Yuan and Bozarth.

Keywords

  • GluN1
  • NMDAR
  • channelopathy
  • intellectual disability
  • molecular dynamics
  • movement disorder
  • positive modulators
  • translational study

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