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 anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamine-expanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab 1C2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia.
Mol Psychiatry 1999 Jan
PMID:Polyglutamine-containing proteins in schizophrenia. 1088 23

Polyglutamine expansion (PGE) encoded by a CAG repeat underlies eight inherited neurodegenerative diseases, among which is Huntington's disease. CAG expansion has also been reported in schizophrenia, suggesting a role for PGE. To investigate the potential role of PGE as a candidate for schizophrenia, we searched for PGE in nuclear families comprising a patient affected by childhood onset schizophrenia (COS, a rare and severe form of the disease) as a variation of the candidate gene approach for identifying susceptibility genes. We tested lymphoblastoid cell lines from COS patients (n = 32) by Western blot analysis with 1C2, a monoclonal antibody that specifically recognizes long polyglutamines. Eight of 11 unrelated black American COS patients showed a 60-kDa (approximately) band indicative of PGE. A strong 60-kDa band (suggestive of a large PGE) was detected in two of the eight positive patients. A weaker 60-kDa band (suggestive of a smaller and non pathogenic PGE) was detected in some unaffected parents or sibs of these two COS patients, and in six other black American COS patients. The strong and weak PGE signals were found to correspond to two different proteins. Unrelated black Americans unaffected by COS (n = 38) were negative for the strong 60-kDa PGE signal. Healthy white Americans (n = 53) were negative for both the strong and weak 60-kDa PGE signals. Two-dimensional gel analysis suggested that the strong PGE signal corresponds to an acidic (pI 4 approximately) protein and resulted in a more precise estimation (52-57 kDa) of its relative mass. This protein appeared to be not represented in Genbank, as suggested by the exclusion of several candidate CAG repeats. Our data suggest that this acidic protein might be a candidate for COS.
Mol Psychiatry 1999 Jan
PMID:Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia? 1088 23

Recent reports indicate an association between second trimester human influenza viral infection and later development of schizophrenia. Postmortem human brain studies also provide evidence for reduction in Reelin mRNA (an important secretory protein responsible for normal lamination of the brain) in schizophrenic brains. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of reelin in day 0 neonatal brains. Prenatally-infected murine brains from postnatal day 0 showed significant reductions in reelin-positive cell counts in layer I of neocortex and other cortical and hippocampal layers when compared to controls. Whereas layer I Cajal-Retzius cells produced significantly less Reelin in infected animals, the same cells showed normal production of calretinin and nNOS when compared to control brains. Moreover, prenatal viral infection caused decreases in neocortical and hippocampal thickness. These results implicate a potential role of prenatal viral infection in causation of neuronal migration abnormalities via reduction in Reelin production in neonatal brains.
Mol Psychiatry 1999 Mar
PMID:Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. 1020 46

The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR=3.8, P=0.001). The effect of loss due to permanent separation (P=0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR=11.0, P=0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR=2.6, P=0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR=3.8, P=0.01), particularly before the age of 9 years (OR=4.3, P=0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n=136; BPD, n=107; SCZ, n=160), yielded few significant findings. Among the controls (n=170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P=0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress.
Mol Psychiatry 1999 Mar
PMID:Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. 1020 40

The proteins expressed by a genome have been termed the proteome. Comparative proteome analysis of brain tissue offers a novel means to identify biologically significant gene products that underlie psychopathology. In this study we collected post mortem hippocampal tissue from the brains of seven schizophrenic, seven Alzheimer's disease (AD) and seven control individuals. Hippocampal proteomes were visualised by two-dimensional gel electrophoresis of homogenised tissue. A mean of 549 (s.d. 35) proteins were successfully matched between each disease group and the control group. In comparison with the control hippocampal proteome, eight proteins in the schizophrenic hippocampal proteome were found to be decreased and eight increased in concentration, whereas, in the AD hippocampal proteome, 35 proteins were decreased and 73 were increased in concentration (P<0.05). One protein, which was decreased in concentration in both diseases, was characterised as diazepam binding inhibitor (DBI) by N-terminal sequence analysis. DBI can regulate the action of the GABA(A) receptor. Protein changes involved 6% of the assessed AD hippocampal proteome, whereas, in schizophrenia protein changes involved less than 1% of the assessed hippocampal proteome. We conclude that schizophrenia has a subtle neuropathological presentation and comparative proteome analysis is a viable means by which to investigate diseases of the brain at the molecular level.
Mol Psychiatry 1999 Mar
PMID:A comparative proteome analysis of hippocampal tissue from schizophrenic and Alzheimer's disease individuals. 1020 49

Activation of the inflammatory response system has been related to the pathophysiology of schizophrenia by several recent studies. Schizophrenic patients have varied levels of proinflammatory cytokines, such as interleukin (IL)-1, -6, and tumor necrosis factor (TNF)alpha in their peripheral blood or cerebrospinal fluid. These cytokines can modify the metabolism of neurotransmitters, influence neural development, and IL-1 has been implicated in acute, and, on the other hand, chronic neurodegeneration. They could therefore be of primary pathogenic importance, either in the acute disease or during those stages of brain development which possibly influence the sensitivity of a person to schizophrenia in later life. The cytokine regulation of brain development and its possible neuroimmune involvement in the pathogenesis of schizophrenia has been raised. One indication of the pathogenic role of IL-1 in schizophrenia would be a demonstration of the difference between schizophrenic patients and healthy controls at the gene level. Therefore we analyzed the polymorphism of the IL-1 gene complex in 50 schizophrenic patients and in 400 healthy blood donors. The following allelisms were analyzed: IL-1beta gene: base exchange polymorphisms at the positions -511 (relative to the transcriptional start site); IL-1alpha gene: base exchange polymorphism at the position -889; IL-1 receptor antagonist (IL-1RA) gene: variable numbers of 86-base pair tandem repeats in intron 2. The frequencies of the IL-1beta (-511) allele 1, IL-1alpha (-889) allele 2, and IL-1RA allele 1 were somewhat, but not significantly, higher in the schizophrenic patients as compared to the controls. These alleles are known to be located on the same haplotype. The number of carriers of this haplotype was significantly higher in the schizophrenia patients (17/50 vs 81/400) than in the controls (P=0.026, chi2). The frequencies of this haplotype were 0.38 and 0.27, respectively (P=0.0266, chi2). The number of homozygotes of this haplotype was significantly higher in the schizophrenia patients (P=0.0006, chi2). These data suggest that the cytokine aberrations in schizophrenia are, at least partly, genetically determined.
Mol Psychiatry 1999 Mar
PMID:Polymorphisms of the interleukin-1 gene complex in schizophrenia. 1020 41

1. The cytochrome P450 monooxygenases, CYP2D6, CYP2C19, and CYP2C9, display polymorphism. CYP2D6 and CYP2C19 have been studied extensively, and despite their low abundance in the liver, they catalyze the metabolism of many drugs. 2. CYP2D6 has numerous allelic variants, whereas CYP2C19 has only two. Most variants are translated into inactive, truncated protein or fail to express protein. 3. CYP2C9 is expressed as the wild-type enzyme and has two variants, in each of which one amino acid residue has been replaced. 4. The nucleotide base sequences of the cDNAs of the three polymorphic genes and their variants have been determined, and the proteins derived from these genes have been characterized. 5. An absence of CYP2D6 and/or CYP2C19 in an individual produces a poor metabolizer (PM) of drugs that are substrates of these enzymes. 6. When two drugs that are substrates for a polymorphic CYP enzyme are administered concomitantly, each will compete for that enzyme and competitively inhibit the metabolism of the other substrate. This can result in toxicity. 7. Patients can be readily phenotyped or genotyped to determine their CYP2D6 or CYP2C19 enzymatic status. Poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (URMs) can be identified. 8. Numerous substrates and inhibitors of CYP2D6, CYP2C19, and CYP2C9 are identified. 9. An individual's diet and age can influence CYP enzyme activity. 10. CYP2D6 polymorphism has been associated with the risk of onset of various illnesses, including cancer, schizophrenia, Parkinson's disease, Alzheimer's disease, and epilepsy.
Cell Mol Neurobiol 1999 Jun
PMID:Polymorphic cytochromes P450 and drugs used in psychiatry. 1031 91

Glutamate receptor function has been hypothesized as an important factor in both the aetiology and treatment of schizophrenia. We have used a multiprobe oligonucleotide solution hybridization (MOSH) technique to examine the regulation of gene expression of the GluR1-7, KA1, and KA2 glutamate receptor subunits in the left rat brain following treatment with the optical isomers of flupenthixol at a dose of 0.2 mg kg-1 day-1 over a period of 4, 12, 24 weeks in order to understand how specific glutamate receptor genes are involved in the treatment of schizophrenia. The GluR2/3 and GluR6/7 subunit immunoreactivity in the right brain following 4 and 24 weeks of drug treatment was also examined by Western blotting. Neither trans- nor cis-flupenthixol was found to alter the gene expression of any of the 9 non-NMDA glutamate receptor subunits. On the other hand, we found a nearly two-fold increase in gene expression of the D2 dopamine receptor in specific brain regions. These results suggest that non-NMDA types of glutamate receptor subunits, in contrast to NMDA receptors, are less likely to have a role in the action of antipsychotic drugs.
Brain Res Mol Brain Res 1999 May 07
PMID:D2 dopamine receptor but not AMPA and kainate glutamate receptor genes show altered expression in response to long term treatment with trans- and cis-flupenthixol in the rat brain. 1032 Jul 79

There have been repeated reports of a decrease in serotonin2A receptors in the frontal cortex from subjects with schizophrenia. Similarly, in rats treated with antipsychotic drugs, it has been shown that many antipsychotic drugs decrease cortical serotonin2A receptors, an affect not seen with the antipsychotic drug haloperidol. We therefore compared the density of serotonin2A receptors in frontal cortex from schizophrenic subjects treated with haloperidol, schizophrenic subjects treated with other antipsychotic drugs, and nonschizophrenic subjects. Independent of antipsychotic drug treatment, serotonin2A receptors were decreased in the frontal cortex from schizophrenic subjects. Importantly, the density of serotonin2A receptors was not different in schizophrenic subjects whether or not they had been treated with haloperidol. This study suggests that data obtained from treating rats with antipsychotic drugs cannot be simplistically extrapolated to studies on tissue obtained postmortem from schizophrenic subjects treated with the same drugs.
Mol Chem Neuropathol
PMID:Decreased serotonin2A receptors in Brodmann's area 9 from schizophrenic subjects. A pathological or pharmacological phenomenon? 1032 13

A shift towards larger CAG/CTG triplet repeats and schizophrenia (SCZ) and bipolar affective disorder (BPAD) has been detected by several recent studies, using the Repeat Expansion Detection (RED) technique, however no specific loci have been shown to be responsible for this shift. Further analyses by our group of RED (CTG)10 ligation products amongst an extended sample of patients and comparison with controls matched for age, sex and ethnicity show no significant differences in distribution (P= 0.23, n=95; P=0.93, n=91, for SCZ and BPAD respectively). Alleles at two recently discovered unstable trinucleotide repeat loci at 18q21.1 (SEF2-1B) and 17q21.3 (ERDA1) have also been analysed in affecteds and matched controls. We observed no increase in frequency of larger alleles (>37 repeats) in affected individuals at SEF2-1B (BPAD: P=0.95, n= 100; SCZ: P=0.61, n=97) or at ERDA1 (BPAD: P= 0.4, n = 101; SCZ: P= 0.05, n = 151, with larger alleles more frequent in controls). Our findings suggest that larger CAG/CTG repeats at these loci are neither major contributory factors to the etiology of psychosis, nor in linkage disequilibrium with a gene that is. Furthermore, when the RED results were compared to allele sizes at SEF2-1B and ERDA1, it was observed that a majority of SCZ, BPAD and control individuals with large RED products had a large allele at either or both sites (78% for RED products > or =270 bp; 62% for RED products > or =180 bp).
Mol Psychiatry 1999 May
PMID:Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder. 1039 12


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