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Review
. 2019 Nov 20:8:F1000 Faculty Rev-1940.
doi: 10.12688/f1000research.18949.1. eCollection 2019.

Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

Scott J Myers  1   2 , Hongjie Yuan  1   2 , Jing-Qiong Kang  3 , Francis Chee Kuan Tan  4 , Stephen F Traynelis  1   2 , Chian-Ming Low  4   5
Affiliations
Review

Distinct roles of GRIN2A and GRIN2B variants in neurological conditions

Scott J Myers et al. F1000Res. .

Abstract

Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.

Keywords: ADHD; GRIN2A; GRIN2B; GluN2A; GluN2B; NMDA receptors; autism; epilepsy; intellectual disability; mutations; neurological disorder; precision medicine; psychiatric disorders; schizophrenia.

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Conflict of interest statement

Competing interests: SFT is PI on a research grant from Allergan and Janssen and Emory University School of Medicine, is a member of the SAB for Sage Therapeutics, is co-founder of NeurOp Inc, and receives royalties for software. SFT and SJM are co-inventors on Emory-owned Intellectual Property that includes allosteric modulators of NMDAR function.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Domains of N-methyl- d-aspartate (NMDA) receptors.
The crystal structure for GluN1/GluN2B receptors is shown in the left panel depicting the amino-terminal domain (ATD), the agonist-binding domain (ABD), and the transmembrane domain (TMD). Not shown is the intracellular carboxyl-terminal domain (CTD). The right panel displays a schematic of a GRIN subunit, and the subdomains and the clamshell features of the ATD and ABD are indicated.
See this image and copyright information in PMC

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    2. F1000 Recommendation

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