Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.
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PMID:Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia. 1110 7

Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population.
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PMID:Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia. 1236 94

The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5' untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: chi(2) = 2.19, P = 0.14; GRIN1/10: chi(2) = 1.5, P = 0.22. For the case-control sample: GRIN1/1: chi(2) = 0.013, P = 0.908; GRIN1/10: chi(2) = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (chi(2) = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses.
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PMID:N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. 1270 33

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.European Journal of Human Genetics (2005) 13, 807-814. doi:10.1038/sj.ejhg.5201418 Published online 20 April 2005.
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PMID: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. 1584 Oct 96

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.
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PMID:Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. 1595 69

Glutamatergic signaling is regulated, in part, through differential expression of NMDA and AMPA/KA channel subunits and G protein-coupled metabotropic receptors. In human brain, region-specific expression patterns of glutamate receptor genes are maintained over the course of decades, suggesting a role for molecular mechanisms involved in long-term regulation of transcription, including methylation of lysine residues at histone N-terminal tails. Using a native chromatin immunoprecipitation assay, we studied histone methylation marks at proximal promoters of 16 ionotropic and metabotropic glutamate receptor genes (GRIN1,2A-D; GRIA1,3,4; GRIK2,4,5; GRM1,3,4,6,7 ) in cerebellar cortex collected across a wide age range from midgestation to 90 years old. Levels of di- and trimethylated histone H3-lysine 4, which are associated with open chromatin and transcription, showed significant differences between promoters and a robust correlation with corresponding mRNA levels in immature and mature cerebellar cortex. In contrast, levels of trimethylated H3-lysine 27 and H4-lysine 20, two histone modifications defining silenced or condensed chromatin, did not correlate with transcription but were up-regulated overall in adult cerebellum. Furthermore, differential gene expression patterns in prefrontal and cerebellar cortex were reflected by similar differences in H3-lysine 4 methylation at promoters. Together, these findings suggest that histone lysine methylation at gene promoters is involved in developmental regulation and maintenance of region-specific expression patterns of ionotropic and metabotropic glutamate receptors. The association of a specific epigenetic mark, H3-(methyl)-lysine 4, with the molecular architecture of glutamatergic signaling in human brain has potential implications for schizophrenia and other disorders with altered glutamate receptor function.
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PMID:Histone methylation at gene promoters is associated with developmental regulation and region-specific expression of ionotropic and metabotropic glutamate receptors in human brain. 1599 84

Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.
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PMID:No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample. 1696 70

Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity.
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PMID:eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? 1732 32

Genetic variation in glutamatergic signalling pathways is believed to play a substantial role in the aetiology of schizophrenia. The N-methyl-D-aspartate receptor subunit gene GRIN1 has been proposed as a candidate gene for schizophrenia. We tested for a potential association between schizophrenia and four single nucleotide polymorphisms (rs4880213, rs11146020, rs6293, and rs10747050) and one microsatellite marker at GRIN1 in a German sample of 354 patients and 323 controls. We found significant associations in single-marker and haplotype-based analyses (P<0.05). Significance was more pronounced (P<0.01) in the subset of patients with a lifetime history of major depression, a subgroup of schizophrenia described previously as a promising phenotypic subtype in genetic studies of schizophrenia. Although significances did not withstand correction for multiple testing, the results of our exploratory analysis warrant further studies on GRIN1 and schizophrenia.
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PMID:Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample. 1772 71

The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology.
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PMID:Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia. 1794 80


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