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J Hum Genet. 2017 Jun;62(6):589-597. doi: 10.1038/jhg.2017.19. Epub 2017 Feb 23.

GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.

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Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Functional Evaluation of Rare Variants, Emory University School of Medicine, Atlanta, GA, USA.
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.


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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