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)

This study follows the observation of an association between homozygosity of an Mscl polymorphism in exon 1 and schizophrenia, which gives rise to a glycine to serine substitution and may alter the functional properties of the receptor. Alternatively the polymorphism may not itself be of functional significance but may be in linkage disequilibrium with another genetic variant in the coding or regulatory regions. To examine the second possibility we have screened all six exons of DRD3 by single-stranded conformational polymorphism analysis (SSCP) in 36 cases and 36 controls. Our findings suggest that the gene is highly conserved since we found no other mutations which alter protein structure. However we did detect a 5-bp deletion in the 3' intronic sequence flanking exon 5 which occurred in 7-8% of subjects within both case and control samples. A single bp substitution (g to a) in exon 3, which does not alter an amino acid was found in one affected individual. In addition we carried out a linkage study of 24 families multiply affected with schizophrenia and a non-parametric linkage study of 90 affected sibling pairs. These studies give no support for either major or moderate gene effects on schizophrenia susceptibility. Finally we have extended our association sample and observe a non-significant excess of homozygotes for the Mscl polymorphism in the sample overall (chi 2 = 2.09, 1 d.f., P = 0.15). The excess of homozygotes is specific to males (chi 2 = 4.617, 1 d.f., P = 0.032) and not females (chi 2 = 0.243, 1 d.f., NS). When these data are added to our previous published data a highly significant excess of homozygotes is observed in males (chi 2 = 13.766, 1 d.f., P = 0.00021) but not females (chi 2 = 0.606, 1 d.f., NS). In conclusion the accumulated data suggest strongly that genetic variation at the DRD3 locus increases susceptibility of schizophrenia, at least in males. At present the Mscl polymorphism in exon 1 of the gene remains a candidate for bringing about functional change in the receptor but this has not been formally tested. Other coding region polymorphisms have not been detected but it remains possible that variation within the promoter may alter receptor function.
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PMID:Linkage, association and mutational analysis of the dopamine D3 receptor gene in schizophrenia. 911 22

Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.
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PMID:The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. 949 16

It is well known that the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine can induce a syndrome in humans that mimics both positive and negative symptoms of schizophrenia. In the light of this observation, it has been hypothesised that schizophrenia might be due to a hypofunction of central glutamate systems. A glycine agonist, by strengthening glutamatergic transmission, has been suggested to be useful as treatment. A crucial issue is the uncertainty regarding the degree of saturation of the glycine site associated with the NMDA receptor. The purpose of this study was to investigate if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site. The effects of systemic and intraventricular administration of glycine. D-serine and L-serine on the hyperactivity induced in mice by the uncompetitive NMDA receptor antagonist MK-801 were tested. Systemically administered glycine and D-serine were found to decrease MK-801-induced hyperactivity. Intraventricularly administered D-serine in doses of 50 or 100 micrograms/side was found to decrease MK-801-induced hyperactivity during the second half hour of registration; L-serine given in the same doses did not affect the MK-801-induced hyperactivity during this period. These data may suggest that the NMDA receptor-associated glycine site is not saturated in vivo.
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PMID:Glycine and D-serine decrease MK-801-induced hyperactivity in mice. 950 65

Folates function as a single carbon donor in the synthesis of serine from glycine, in the synthesis of nucleotides form purine precursors, indirectly in the synthesis of transfer RNA, and as a methyl donor to create methylcobalamin, which is used in the re-methylation of homocysteine to methionine. Oral folates are generally available in two supplemental forms, folic and folinic acid. Administration of folinic acid bypasses the deconjugation and reduction steps required for folic acid. Folinic acid also appears to be a more metabolically active form of folate, capable of boosting levels of the coenzyme forms of the vitamin in circumstances where folic acid has little to no effect. Therapeutically, folic acid can reduce homocysteine levels and the occurrence of neural tube defects, might play a role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis, appears to be a rational aspect of a nutritional protocol to treat vitiligo, and can increase the resistance of the gingiva to local irritants, leading to a reduction in inflammation. Reports also indicate that neuropsychiatric diseases secondary to folate deficiency might include dementia, schizophrenia-like syndromes, insomnia, irritability, forgetfulness, endogenous depression, organic psychosis, peripheral neuropathy, myelopathy, and restless legs syndrome.
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PMID:Folates: supplemental forms and therapeutic applications. 963 Jul 38

Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.
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PMID:Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. 1039 14

High levels of D-serine are found in mammalian brain, where it is an endogenous agonist of the strichinine-insensitive site of N-methyl D-aspartate type of glutamate receptors. D-serine is enriched in protoplasmic astrocytes that occur in gray matter areas of the brain and was shown to be synthesized from L-serine. We now report cloning and expression of human serine racemase, an enzyme that catalyses the synthesis of D-serine from L-serine. The enzyme displays a high homology to the murine serine racemase. It contains a pyridoxal 5'-phosphate attachment sequence similar to bacterial biosynthetic threonine dehydratase. Northern-blot analysis show high levels of human serine racemase in areas known to contain large amounts of endogenous D-serine, such as hippocampus and corpus callosum. Robust synthesis of D-serine was detected in cells transfected with human serine racemase, demonstrating the conservation of D-amino acid metabolism in humans. Serine racemase may be a therapeutic target in psychiatric diseases as supplementation of D-serine greatly improves schizophrenia symptoms. We identify the human serine racemase genomic structure and show that the gene encompasses seven exons and localizes to chromosome 17q13.3. Identification of the intron-exon boundaries of the human serine racemase gene will be useful to search for mutations in neuropsychiatric disorders.
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PMID:Human serine racemase: moleular cloning, genomic organization and functional analysis. 1105 47

Persistent negative symptoms and cognitive dysfunction are a major cause of chronic disability in schizophrenia. Atypical antipsychotics such as clozapine, risperidone, and olanzapine induce significantly greater improvement in negative symptoms than that which is obtained with conventional agents. However, it remains unclear whether these agents treat core negative symptoms of schizophrenia, or simply induce less secondary psychopathology. A second approach for treatment of persistent negative symptoms is the use of N-methyl-d-aspartate (NMDA) receptor-stimulating agents, such as glycine, d-serine or d-cycloserine. These agents, when added to conventional or atypical antipsychotics, may induce significant additional reduction in both negative and cognitive symptoms.
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PMID:Treatment of negative and cognitive symptoms. 1112 2

Prepulse inhibition (PPI) of the startle response is used as a measure of sensorimotor inhibitory processes. Deficits in PPI have been found in patients with schizophrenia, obsessive compulsive disorder (OCD) and Huntington's disease. PPI can also be disrupted in animals through manipulations that augment serotonergic activity, such as administration of the serotonin (5-HT) agonists 8-OH-DPAT, RU 24969 and DOI. In the present experiment the identity of the 5-HT receptor subtype that mediates the DOI-induced disruption of PPI was examined. Dose-response studies revealed that the novel 5-HT(2A) antagonist, MDL 100,907 (0.01, 0.1 and 1.0mg/kg, s.c.), but not the new 5-HT(2C) antagonist SDZ SER 082 (0.125, 0.25 and 0.5mg/kg, s.c.), prevented the loss of PPI induced by DOI (0.25 or 0.5mg/kg, s.c.). The results support the hypothesis that the 5-HT(2A) receptor is involved in the modulation of sensorimotor gating. Because deficits in PPI are used as a model of sensorimotor gating abnormalities found in schizophrenia, the present study supports the view that MDL 100,907 may be a novel atypical antipsychotic. Studies of the serotonergic substrates of PPI may provide a model of the possible serotonergic role in the sensorimotor gating abnormalities in schizophrenia and OCD patients.
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PMID:DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT(2A) and not by 5-HT(2C) receptors. 1122 88

Recently a new variant of Creutzfeldt-Jakob disease, a human prion disease, with prominent psychiatric manifestations in the early stage was identified, suggesting that human prion disease may be associated with mental disorders. Furthermore, a novel missense mutation with asparagine-to-serine substitution at codon 171 of the human prion gene (N171S) was identified in a family with severe psychiatric symptoms. This finding provides further clue that the prion gene may be a susceptibility gene for certain psychiatric disorders. We systematically sequenced the protein-coding and untranslated exons of prion gene in 62 Han Chinese schizophrenic patients with positive family history from Taiwan. We identified two polymorphisms that alter amino acid sequences, a methionine/valine at codon 129 (M129V) and a glutamate/lysine at codon 219 (E219K), respectively. Further comparison of the genotype, allele and haplotype frequency distributions of these two polymorphisms between 234 schizophrenic patients and 100 non-psychotic controls, however, did not reveal significant differences between two groups. Besides, no other mutations in the prion gene were identified in these 62 patients. Hence, our results suggest that the prion gene may not play a major role in conferring susceptibility to schizophrenia.
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PMID:Lack of evidence to support the association of the human prion gene with schizophrenia. 1124 88

Epidemiological studies have shown a lower prevalence of tardive dyskinesia (TD) among Chinese psychiatric patients compared to Caucasian and Black patient populations. It has been hypothesized that pharmacogenetic factors may underlie this cross-cultural difference. Due to the important implications of the dopamine D3 receptor gene (DRD3) in motor control, we investigated the frequency of polymorphic serine (ser) to glycine (gly) substitution of the gene DRD3 in Chinese schizophrenic patients. The sample size consisted of 65 patients with TD and 66 without TD. Patients were assessed for the severity of TD, the presence of akathisia and parkinsonian symptoms and were subsequently genotyped. We found no evidence that the dopamine D3 receptor gene is likely to confer susceptibility to the development of tardive dyskinesia in Chinese patients with schizophrenia.
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PMID:Dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients. 1147 19


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