Distinct roles of GRIN2A and GRIN2B variants in neurological conditions.

Scott J Myers,Stephen F Traynelis,Francis Chee Kuan Tan,Hongjie Yuan,Jing-Qiong Kang,Chian-Ming Low

doi:10.12688/f1000research.18949.1

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.

Highlights

Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission throughout the central nervous system. These receptors can be classified into at least three distinct families, and nomenclature is based on the initial discovery of selective activating agonists AMPA, kainate, and N-methyl-D-aspartate (NMDA) for their corresponding receptors, which arise from GRIA, GRIK, and GRIN genes, respectively
In terms of the evolutionary history of the NMDA receptor (NMDAR), it appears that four GluN2 paralogs (GluN2A–D) were produced by two rounds of gene duplication in a common vertebrate ancestor; the rounds diverged during early vertebrate evolution principally at their carboxyl-terminal domain (CTD)[3]
Comparison of patient phenotype for GRIN2A and GRIN2B missense and nonsense variants Among the variants identified in the GRIN gene family, those in GRIN2A (46%) and GRIN2B (38%) account for the vast majority, followed by GRIN1 variants (14%; ClinVar)[72]

Summary

Introduction

Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission throughout the central nervous system. An assessment of the genetic variation in the healthy population together with an evaluation of GRIN2A and GRIN2B variants in patients with neurological disease provides information about the regional tolerance of different domains of the GluN2 subunit This approach reveals insight into protein function and information about the regions of the receptor that cannot tolerate even modest changes in amino acid side chain properties[81]. Variants at the same residue position in GluN2A and GluN2B resulted in different disease phenotypes A variant in both GRIN2A and GRIN2B that occurs at the same homologous position of these GluN2 subunits in NMDAR has been identified Both GluN2A-N615K and GluN2B-N615I and GluN2B-N615K variants that substitute an evolutionarily conserved asparagine in the membrane re-entrant loop resulted in a loss of Mg2+ block[21,75,80,84]. This supports a role for this medication as a potential therapy to mimic a loss Mg2+ block at the potentials in neurons

PubMed Abstract

26. Schneggenburger R

52. Hardingham GE

Findings

56. Dumas TC