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)

Genetic linkage, molecular analysis, and in situ hybridization have identified TYR and D11S388 as markers flanking the chromosome 11 breakpoint in a large pedigree where a balanced translocation, t(1;11)(q43;q21), segregates with schizophrenia and related affective disorders. Somatic cell hybrids, separating the two translocation chromosomes from each other and from the normal homologues, have been produced with the aid of immunomagnetic sorting for chromosome 1- and chromosome 11-encoded cell-surface antigens. The genes for two of these antigens map on either side of the 11q breakpoint. Immunomagnetic bead sorting was also used to isolate two stable X-irradiation hybrids for each cell-surface antigen. Each hybrid carries only chromosome 11 fragments. Translocation and X-irradiation hybrids were analyzed, mainly by PCR, for the presence of 19 chromosome 11 and 4 chromosome 1 markers. Ten newly designed primers are reported. The X-irradiation hybrids were also studied cytogenetically, for human DNA content, by in situ Cot1 DNA hybridization and by painting the Alu-PCR products from these four lines back onto normal human metaphases. The generation of the translocation hybrids and of the chromosome 11q fragment hybrids is a necessary preliminary to determining whether a schizophrenia-predisposition gene SCZD2 is encoded at this site.
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PMID:Schizophrenia-associated chromosome 11q21 translocation: identification of flanking markers and development of chromosome 11q fragment hybrids as cloning and mapping resources. 838 24

1. Evidence suggests catecholamines and indoleamines may play a role in the pathogenesis of several psychiatric disorders. These neurotransmitters (i.e. dopamine, norepinephrine and serotonin) are synthesized within the human brain from their precursors, the aromatic large neutral amino acids tyrosine and tryptophan. Other large neutral amino acids, namely valine, isoleucine, leucine and phenylalanine affect precursor availability by competing with tryptophan and tyrosine for the transport system across the blood brain barrier. 2. The authors evaluated the brain availability of L-tryptophan and tyrosine in a sample of psychiatric patients with a diagnosis of major depression and schizophrenia. 3. The present results suggest a possible usefulness of Tryptophan/Large Neutral Amino Acids ratio in distinguishing major depression from schizophrenia, while Tyrosine/Large Neutral Amino Acids ratio shows a very limited usefulness. The absolute need of powerful and accurate statistical analysis to evaluate the power of a biological test clearly stands out from the present study.
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PMID:Neutral amino acid availability in two major psychiatric disorders. 858 60

A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P=0.041, odds ratio=1.28, 95% confidence interval 1.012-1.623).
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PMID:Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. 865 41

Neurotensin (NT, pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) is a tridecapeptide that displays a wide spectrum of biological actions. Cyclic derivatives of a hexapeptide NT [(8-13)] (N alpha MeArg-Lys-Pro-Trp-Tle-Leu, Tle = tert-leucine) were designed and prepared by a combination of solution and solid-phase peptide synthetic methodologies. As reported previously, several analogs possessed nanomolar binding affinities for NT receptors in newborn (10-day-old) mouse brain membrane preparations. In this study, we determined the functional ability of these analogs to mobilize intracellular free calcium, [Ca2+]i, in HT-29 cells (human colonic adenocarcinoma). Of greatest interest were the cyclic compounds 2, 6 and 9 that had Ki values of 0.19, 3.50 and 4.18 microM for [3H]NT labeled receptors in the HT-29 cell membrane assay, respectively. In the functional assay, compounds 2 and 6 mobilized [Ca2+] with EC50 values of 0.13 and 20 microM, respectively. In comparison, Compound 9 blocked the NT-induced mobilization of [Ca2+]i, with an IC50 of 1.70 microM. The present findings indicate that small molecule cyclic analogs, that possess functional activity, can be designed and may have therapeutic utility in the treatment of schizophrenia and possibly other neurological disorders.
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PMID:Functional activity of new C-terminal cyclic-neurotensin fragment analogs. 881 44

In a series of studies tyrosine transport was investigated in patients with schizophrenia. Plasma amino acids competing with tyrosine for transport with the L-system were found to be elevated, and correlated negatively with homovanillic acid levels in the cerebrospinal fluid of the patients. The results were interpreted as a decrease in the transport of tyrosine to the brain leading to a reduced dopamine turnover. In in vitro studies with fibroblasts the transport capacity of tyrosine was found to be decreased (a lower Vmax value) in the patients. No changes in transport mechanism for the other neutral amino acids were found. The finding of a lower transport capacity in patients was replicated in a new sample in whom tyrosine transport also was determined in vivo with positron emission tomography. The in vivo studies demonstrated a decrease in the influx of tyrosine across the blood-brain barrier. Altogether the results were interpreted in support of the view of schizophrenia as a systemic disorder with a primary disturbance in cell membrane function.
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PMID:Tyrosine transport as an indicator of cell membrane dysfunction in schizophrenia. 888 23

Two independent studies reported recently have shown a significant decrease in Vmax of tyrosine transport in fibroblasts grown from schizophrenics' skin compared with controls. It has also been shown that tyrosine transport into the brain is decreased in schizophrenics compared with controls. In view of the importance of these findings in elucidating the biochemical mechanism(s) associated with schizophrenia, we have studied the kinetics of tyrosine transport and the levels of monoamine oxidase (MAO) activity in fibroblasts grown from the skins of schizophrenics and unrelated control subjects. Using the Lineweaver-Burk plot, the Eadie Hostee plot and the Hanes plot we have calculated the Km and Vmax for tyrosine transport. We have found a significant decrease in the Km and Vmax values for tyrosine transport in schizophrenics compared with control fibroblast samples. No changes were observed in the levels of MAO. Using Lineweaver-Burk plot (1/S Versus 1/V) it has been shown that the tyrosine transport inhibition is uncompetitive. This finding proposes that the inhibition is in the substrate transport protein complex, which may be taking place during the transit of the substrate through the cell membrane. From the observed findings and from the literature evidence we suggest that the altered metabolism of phospholipids in schizophrenics, such as deficiency of arachidonic acid and docosahexaenoic acid, may be contributing to this observed phenomena.
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PMID:Decreased tyrosine transport in fibroblasts from schizophrenics: implications for membrane pathology. 888 24

Six allelic fragments were typed by a polymerase chain reaction process with a pair of primers specific for a sequence containing the polymorphic (GT)n repeat, a microsatellite repeat, in the human dopamine beta-hydroxylase (DBH) gene. Their frequencies in unrelated patients with schizophrenia were 0.003 (A1), 0.114 (A2), 0.343 (A3), 0.526 (A4), 0.006 (A5), and 0.009 (A6), and in unrelated control subjects, 0.012 (A1), 0.086 (A2), 0.309 (A3), 0.574 (A4), 0.006 (A5), and 0.012 (A6). Kruskal-Wallis analysis revealed significant differences among the three groups, the drug-free and drug-treated patients, and the control subjects, in serum DBH activity of the subjects whose genotype was A2/A3 (H = 6.0, p < .05) or A3/A3 (H = 9.8, p < .01), in serum homovanillic acid concentration of those whose genotype was A3/A4 (H = 7.7, p < .025), and in serum tyrosine concentration of those whose genotype was A4/A4 (H = 8.3, p < .02). Mann-Whitney U test showed that in the subjects carrying the A3/A4 genotype, serum noradrenaline concentration of drug-treated patients was significantly higher than that of control subjects (N = 58, p < .02). These results suggest that genotypic polymorphism of the human DBH is likely to be associated with biochemical variability of the catecholamine pathway in schizophrenia.
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PMID:Is the polymorphic microsatellite repeat of the dopamine beta-hydroxylase gene associated with biochemical variability of the catecholamine pathway in schizophrenia? 908 94

The dopamine (DA) neurons projecting to the prefrontal cortex (PFC) are thought to be involved in working memory, stress response, and the pathogenesis of schizophrenia. In this commentary, we review the current evidence supporting a precursor tyrosine dependence of these mesoprefrondal DN neurons. Several studies in rats employing different experimental paradigms [i.e. experimental diabetes and early-treated phenylketonuria (PKU) model] have shown that reduced tyrosine levels in brain can affect markedly the physiology and functions of these DA neurons. However, supplemental tyrosine is effective in enhancing functional transmitter outflow from mesoprefrontal DA neurons only under conditions where their physiological activity is enhanced and DA synthesis and release are uncoupled from intrinsic regulatory controls. Recent studies in humans have also suggested that variations in brain tyrosine levels can affect significantly higher cortical functions subserved by the PFC. In early-treated PKU patients with mildly reduced tyrosine levels, marked impairments in cognitive functions dependent on the dorsolateral PFC could be detected. In drug-treated schizophrenic patients, supplemental tyrosine was shown to have a disruptive effects on the smooth-pursuit eye movement performance task. Furthermore, tyrosine administration was effective in restoring impaired working memory in humans following cold stress paradigm, as assessed by a computer-based delayed matching to-sample memory task. These human studies, together with the current evidence obtained from animal experiments, suggest that the functions of the mesoprefrontal DA neurons can, under certain circumstances, be readily influenced by the availability of the precursor tyrosine.
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PMID:Mesoprefrontal dopaminergic neurons: can tyrosine availability influence their functions? 910 94

The brain-rich 14-3-3 protein regulates synthesis and excretion of bioamine by activating tyrosine and tryptophan hydroxylases, and by exocytosis of catecholamines and serotonin. In humans, at least eight subunits of the 14-3-3 protein family have been isolated. The 14-3-3 eta chain gene is located at 22q12.1 to q13.1, one of the chromosome regions identified as possibly linked to schizophrenia. We systematically searched for nucleotide variants in the coding region, 5' and 3' untranslated region, and in the exon-intron boundaries of the genomic 14-3-3 eta gene in 24 schizophrenics and 24 controls. Two polymorphic sites were found: one in the 5' untranslated region and one in the 3' untranslated region. However, no variants predicting amino-acid alterations were observed. Similar allelic and genotypic distributions for both polymorphisms were found in 308 schizophrenics and 135 controls.
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PMID:Systematic search for mutations in the 14-3-3 eta chain gene on chromosome 22 in schizophrenics. 956 86

Mutation screening identified variants of h5-HT1A (Gly-22-Ser, Ile-28-Val, Arg-219-Leu), h5-HT1B (Phe-124-Cys), h5-HT2A (Thr-25-Asn, His-452-Tyr), h5-HT2C (Cys-23-Ser) and h5-HT7 (Thr-92-Lys, Pro-279-Leu) receptors. Screening of h5-HT1D, h5-ht1e, h5-ht1f and h5-ht5 receptor genes failed to detect any significant mutations. No differences in radioligand binding properties were observed between the h5-HT1A Ile-28-Val variant receptor (VR) and the wildtype receptor (WTR). Binding profiles of the h5-HT1A Gly-22-Val variant and the WTR were also very similar, but the 8-OH-DPAT-induced down-regulation and desensitization of the VR was attenuated. The h5-HT1B Phe-124-Cys variant leads to considerable changes in [3H]5-carboxamidotryptamine binding: Bmax was decreased and the affinity of various h5-HT1B ligands was modified (usually increased; e.g., in the case of sumatriptan). The h5-HT2A His-452-Tyr variant causes an alteration of the amplitude and timing of intracellular calcium mobilization in platelets from 452-His/452-Tyr heterozygous compared to 452-His/452-His homozygous individuals. Most, but not all, of the VRs listed above were examined for association with, e.g., bipolar depression and schizophrenia, yet no relation was observed. The most consistent finding was an association between a silent mutation (102T/C) in the h5-HT2A receptor gene and schizophrenia; this association may be explained by linkage disequilibrium with a functional variant in the regulatory region of the gene. Studies of the therapeutic response to clozapine produced no homogeneous results with respect to the pharmacogenetic significance of the various mutations in the h5-HT2A and h5-HT2C receptor genes.
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PMID:Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role. 992 35


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