Abstract
N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.
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Acknowledgements
We are grateful to Kelli Dejohn, Shantel Brown, Carmela Brito, Joanne Baez, Jing Zhang and Barrington Burnett for clinical and technical assistance, and critical analysis. We especially thank the families of our patients for the loving care for their children and cooperation with our work. During this work, WC was supported by the Xiangya-Emory Medical Schools Visiting Student Program; HY was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH-R01HD082373, by the Emory+Children’s Pediatric Center Seed Grant Program, by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454, by NIH HHSN268201400169P; SFT was supported by NIH-NINDS R01NS036654, R24NS092989 and R01NS092989. TMP and CS were funded by the Cedars-Sinai institutional funding program and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Author contributions
SFT, SAS, HY and TMP designed the experiments and wrote the paper. WC, SAS, AT and HY performed the biological experiments and analyzed biological data. CS and TMP collected clinical information and data. CS, JMG, SMK, MT, MA, MM and TMP evaluated the patients, provided clinical assessments and whole-exome sequencing data. All authors discussed the results and implications and commented on the manuscript.
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SFT is a consultant for Janssen Pharmaceuticals, NeurOp, Inc., and Pfizer Inc, and co-founder of NeurOp Inc. The remaining authors declare no conflict of interest.
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Chen, W., Shieh, C., Swanger, S. et al. GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function. J Hum Genet 62, 589–597 (2017). https://doi.org/10.1038/jhg.2017.19
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DOI: https://doi.org/10.1038/jhg.2017.19
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