Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia

Abstract

NMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3' region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted. Molecular Psychiatry (2001) 6, 211-216.The glutamate dysfunction hypothesis is one of the main explanatory hypotheses for the pathophysiology of schizophrenia. It originated from the observation that phencyclidine (PCP) intoxication closely mimics schizophrenia. 1 At serum levels that produce schizophrenic symptoms, PCP acts as a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptors. 2 Ketamine and MK-801, two additional noncompetitive antagonists of NMDA receptors, also produce schizophrenic symptoms and exacerbate symptoms in patients with schizophrenia. [3][4][5] NMDA receptors, together with alpha-amino-3-hydroxy-5-methyl-4-isozaxole propionic acid (AMPA) and kainate receptors, comprise the known ionotropic glutamate receptors. 6 Functional NMDA receptors are composed of a common NMDAR1 subunit and one of four NMDAR2 subunits (NMDAR2A-NMDAR2D) combined in an undetermined ratio to make the heteromeric receptor complex. 7,8 Knockout mice lacking each of the known NMDA receptor subunits have been generated. 9-15 Mice lacking NMDAR1 or NMDAR2B protein die perinatally, 9,10,14 knockdown mice expressing only 5% of normal levels of the essential NMDAR1 subunit survive to adulthood but display behavioral abnormalities including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior. 16 NMDAR2B mRNA is found throughout the entire embryonic brain in mice, but its expression becomes restricted to the forebrain postnatally. 17,18 There is a high degree of regional specialization with respect to specific NMDA receptors within the basal ganglia, and NMDAR2B is abundant in the striatum. 19 NMDAR2B mRNA expression is regulated by cortico-striata...

Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: A HuGE review and meta-analysis

“…3, available online only), we did not find any strong haplotype structure for SNPs 2664C/T, 4197T/C, and 5988T/C, although they were previously reported to be in almost complete LD with SNPs 1665C/T and 5806A/C. 21 None of the three individual markers (366C/G, 2664C/T, and 5988T/C) provided significant evidence. Both allele and haplotype frequencies may vary around the world, and the markers could be in LD with different haplotypes in different populations.…”

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.…”

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

“…A positive association between schizophrenia and variants in coding exons and variants in the 3′-untranslated region of the NR2B gene suggests that the NR2B gene locus, when in linkage disequilibrium with these regions, confers susceptibility to schizophrenia. 18 Whether these variants and the T-200G variant are in linkage disequilibrium remains unknown. Therefore, further study in the same sample is required to determine the association among these variants in the NR2B gene.…”

“…17 However, Ohtsuki et al reported eight variants encoding exons in the 3′-untranslated region of the hNR2B gene, some of which were significantly associated with schizophrenia. 18 In the present study, we sequenced 5′-upstream nucleotides of the hNR2B gene and identified a novel T-200G variant that was significantly associated with schizophrenia. We suggest that this variant is involved in glutamate dysfunction leading to the development of schizophrenia.…”