Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients

Rice, Sharmon R.; Niu, Ningning; Berman, Daniel; Heston, Leonard L.; Sobell, Janet L.

doi:10.1038/sj.mp.4000838

Cited by 45 publications

(22 citation statements)

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“…Others who have recently studied individual members of the GRIN family have also found a low rate of nonsynonymous SNPs. 22,25 For example when the GRIN1 gene was screened for mutations in 142 chromosomes from the Caucasian population, Rice and colleagues 25 found no non-synonymous changes and only two synonymous changes. A third synonymous change was found by genotyping a further 72 Caucasian chromosomes.…”

Section: Discussionmentioning

confidence: 99%

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Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor

et al. 2002

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The glutamatergic system is the major excitatory neurotransmitter system in the CNS. Glutamate receptors, and in particular N-methyl-D-aspartate (NMDA) receptors, have been proposed as mediators of many common neuropsychiatric phenotypes including cognition, psychosis, and degeneration. We have reconstructed the genomic structure of all five genes encoding NMDA receptors in silico. We screened each for sequence variation and estimated the allele frequencies of all detected SNPs in pooled samples of 184 UK Caucasian schizophrenics and 184 UK Caucasian blood donor controls. Only a single non-synonymous polymorphism was found indicating extreme selection pressure. The rarity of non-synonymous changes suggests that such variants are unlikely to make a common contribution to common phenotypes. We found a further 26 polymorphisms within exonic or adjacent intronic sequences. The minor alleles of most of these have a relatively high frequency (63% above 0.2). These SNPs will therefore be suitable for studying neuropsychiatric phenotypes that are putatively related to NMDA dysfunction. Pooled analysis provided no support for association between any of the GRIN genes and schizophrenia.

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Section: Discussionmentioning

confidence: 99%

“…For comparison with our data, we have re-calculated the coding sequence diversity values for Caucasian subjects in that study. 25 For synonymous changes, = 1.2 × 10 −4 and ⌸ = 2.8 × 10 −4 , for non-synonymous changes, both and ⌸ are zero. The results are therefore similar to our own analysis of NMDA genes.…”

Section: Discussionmentioning

confidence: 99%

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor

et al. 2002

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“…16,18,20 The primer sets were designed to amplify the SNP-containing regions. The NCBI number of the SNP sites, corresponding primer sequences and the sizes of the amplicons are presented in Supplementary material 1.…”

Section: Subjectsmentioning

confidence: 99%

An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray

Qin

Pan

et al. 2005

Eur J Hum Genet

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Dysfunction of the N-methyl-D-aspartate (NMDA) receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of several antagonists and on observation of genetic animal models. To conduct association analysis of the NMDA receptors in the Chinese population, we examined 16 reported SNPs across the NMDA receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B), five of which were identified in the Chinese population. In this study, we combined universal DNA microarray and ligase detection reaction (LDR) for the purposes of association analysis, an approach we considered to be highly specific as well as offering a potentially high throughput of SNP genotyping. The association study was performed using 253 Chinese patients with schizophrenia and 140 Chinese control subjects. No significant frequency differences were found in the analysis of the alleles but some were found in the haplotypes of the GRIN2B gene. The interactions between the GRIN1 and GRIN2B genes were evaluated using the multifactor-dimensionality reduction (MDR) method, which showed a significant genetic interaction between the G1001C in the GRIN1 gene and the T4197C and T5988C polymorphisms in the GRIN2B gene. These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.

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“…Some genetic analyses have disclosed that single-nucleotide or dinucleotide-repeated polymorphisms of the NMDA receptor subunit gene increase susceptibility to schizophrenia (Rice et al, 2001;Itokawa et al, 2003).…”

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Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca²⁺/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine

Mouri

Noda

et al. 2007

Mol Pharmacol

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Continuous ingestion of phencyclidine (PCP) in humans produces long-lasting schizophrenic-like cognitive dysfunction. Although a malfunction of dopaminergic and/or glutamatergic neurotransmission is implicated in the etiology of schizophrenia, involvement of the dopaminergic-glutamatergic neurotransmission in the cognitive dysfunction induced by repeated PCP treatment is minor. We demonstrated that mice treated with PCP (10 mg/kg/day s.c.) for 14 days displayed an impairment of latent learning in a water-finding task and of learningassociated phosphorylation of Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) and NR1 in the prefrontal cortex even after drug withdrawal. The infusion of a CaMKII inhibitor and NR1 antisense oligonucleotide into the prefrontal cortex produced an impairment of latent learning and decrease of learning-associated phosphorylation of CaMKII, which were observed in the PCP-treated mice. Exogenous NMDA-induced CaMKII activation was not observed in slices of the prefrontal cortex prepared from mice treated repeatedly with PCP. The potentiation of NMDA receptor function by the infusion of glycine into the prefrontal cortex ameliorated these impairments in mice treated repeatedly with PCP. The high potassium-stimulated release of dopamine from the prefrontal cortex was less extensive in the PCP-treated than saline-treated mice. The infusion of a dopamine-D1 receptor agonist into the prefrontal cortex attenuated the impairment of latent learning and decrease of learning-associated NR1 phosphorylation in the PCPtreated mice, suggesting a functional linkage between glutamatergic and dopaminergic signaling. These findings indicate that repeated PCP treatment impairs latent learning through a prefrontal cortical dysfunction of NMDA-CaMKII signaling, which is associated with dopaminergic hypofunction.Schizophrenia is characterized by severe and persisting deficits in cognitive functions (Winterer and Weinberger, 2004). Several lines of evidence suggest that the N-methyl-D-aspartate (NMDA) receptor is involved in the pathogenesis of schizophrenic cognitive dysfunction. Postmortem studies in patients with schizophrenia have identified altered expression patterns of NMDA receptor subunits (Dracheva et al., 2001) and decreased levels of phosphorylated NR1, an essential NMDA receptor subunit (Emamian et al., 2004) in the prefrontal cortex, which is considered to be the region contributing most to the pathophysiology of schizophrenic

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Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients

Cited by 45 publications

References 28 publications

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor

An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray

Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca²⁺/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine

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Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients

Cited by 45 publications

References 28 publications

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor

An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray

Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca2+/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine

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Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca²⁺/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine