Format

Send to

Choose Destination
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.

Author information

1
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
2
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
3
David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
4
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
6
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
7
Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
8
Center for Functional Evaluation of Rare Variants, Emory University School of Medicine, Atlanta, GA, USA.
9
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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.

PMID:
28228639
PMCID:
PMC5637523
DOI:
10.1038/jhg.2017.19
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center