Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia

Abstract

N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis of schizophrenia. We determined the nucleotide sequence of the 5′-upstream region of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G variant located in one of the Sp1 binding sites. To investigate the effect of this variant on the transcriptional activity of the hNR2B gene, we performed gene reporter assays using PC12 pheochromocytoma cells transiently transfected with luciferase reporter plasmids. In the absence of nerve growth factor (NGF), luciferase activities did not significantly differ between the two alleles and the control plasmid. However, luciferase reporter activity of the T allele was significantly up-regulated compared to that of the G allele in the presence of NGF (P = 0.0013), indicating that this polymorphic site is a critical region for NR2B gene regulation through NGF-induced Sp1-binding. A case control study showed that the frequency of the G allele (P = 0.0164) was significantly higher in 100 schizophrenics than in 100 controls. These findings suggest that the T-200G variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and may be involved in the development of schizophrenia. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings.

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

“…44 An overlap in genetic susceptibility for schizophrenia and BPI has been argued by many investigators and was recently reviewed by Craddock et al 45 We agree that there is strong evidence for an overlap of genetic factors contributing to these two phenotypes, and we recently published a candidate gene association study 17 that investigated 440 SNPs in 64 functional and positional candidates for both disorders, genotyped in two sets of triads of AJ descent ascertained for either BPI or schizophrenia. Although at that time studies had suggested GRIN2B only as a candidate for schizophrenia, 40,41 in our study, it was among the best findings for BPI. More recently, a study by Martucci et al 23 also detected an association between GRIN2B DNA variants and both BP and schizophrenia, and a metaanalysis supported the association with schizophrenia.…”

No association of three GRIN2B polymorphisms with lithium response in bipolar patients

“…However, in molecular-genetic studies, the functionality of only the -200T/G polymorphism has been described. This variant was found to be localized in the putative Sp1 binding site in the 5'-upstream region of the GRIN2B gene, and different luciferase reporter activity was found for different alleles, suggesting that this region is crucial for GRIN2B regulation [11]. For the other two polymorphisms, there are no experimental data on their importance in gene regulation; however, such influence cannot be excluded.…”

“…The three GRIN2B polymorphisms, 366C/G (Pro122) (rs7301328), rs890G/T and -200T/G (rs1019358), were analyzed by PCR-RFLP analysis according to Ohtsuki et al [13], with minor modifications. The SNP selection was based on the functionality of the -200G/T polymorphism [9,11] and the fact that the other two polymorphisms (rs7301328 and rs890) showed positive association with schizophrenia [1,13], which may have some common genetic background with bipolar disorder.…”

Psychosis and relapse in bipolar disorder are related to GRM3, DAOA, and GRIN2B genotype

“…16,22,23 Miyatake et al have observed that the T allele of the GRIN2B rs1019385 SNP results in increased luciferase transporter activity in the presence of nerve growth factor (NGF). 24 The presence of a G allele had no effect on reporter activity, suggesting that GRIN2B rs1019385 may have a role in transcriptional control of the GRIN2B transcript. 24 The G72 gene product, D-amino-acid oxidase activator (DAOA), activates the peroxisomal protein D-amino-acid oxidase (DAO).…”

“…24 The presence of a G allele had no effect on reporter activity, suggesting that GRIN2B rs1019385 may have a role in transcriptional control of the GRIN2B transcript. 24 The G72 gene product, D-amino-acid oxidase activator (DAOA), activates the peroxisomal protein D-amino-acid oxidase (DAO). 25 This protein (G30) degrades D-serine, which acts, similar to glycine, as a coactivator on the "glycine binding site" of the glutamatergic NMDA receptor.…”