Journal
JOURNAL OF HUMAN GENETICS
Volume 62, Issue 6, Pages 589-597Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jhg.2017.19
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Categories
Funding
- Xiangya-Emory Medical Schools Visiting Student Program
- Eunice Kennedy Shriver National Institute of Child Health & Human Development [NIH-R01HD082373]
- Emory+Children's Pediatric Center
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000454]
- Cedars-Sinai institutional funding program
- Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases
- [NIH HHSN268201400169P]
- [NIH-NINDS R01NS036654]
- [R24NS092989]
- [R01NS092989]
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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 similar to 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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