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)

Overexpression of the D2 dopamine receptor has been proposed to be part of the pathology of schizophrenia. The isolation of a D2 dopamine receptor clone has assisted the molecular characterization of D2 receptor. We have now isolated an identical rat clone along with two other clones--a second related rat clone (RD-2in) and a homologous bovine clone (BD-2in), both of which contain an insert encoding an additional 29 amino acids relative to the original rat clone (RD-2o). All three clones encode D2 receptor binding sites when expressed in COS-7 cells. The amino-acid insert encoded by D-2in lies in the domain of the receptor believed to interact with the GTP-binding proteins (G proteins) of various signal transduction pathways. By using oligonucleotide probes specific for either D-2o or D-2in RNA transcripts, we have found that the level of expression of the D-2in-encoded form of the receptor is seven times that of the D-2o form in the caudate nucleus, the richest brain source of D2 receptors.
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PMID:A second molecular form of D2 dopamine receptor in rat and bovine caudate nucleus. 213 98

The importance of the dopaminergic system in brain function has been emphasized by its association with neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. On the basis of their biochemical and pharmacological characteristics, dopamine receptors are classified into D1 and D2 subtypes. As the most abundant dopamine receptor in the central nervous system, D1 receptors seem to mediate some behavioural responses, modulate activity of D2 dopamine receptors, and regulate neuron growth and differentiation. The D dopamine receptor has been cloned by low-stringency screening. We report here the cloning of human and rat D1 dopamine receptors by applying an approach based on the polymerase chain reaction. The cloned human D1 dopamine receptor has been characterized on the basis of four criteria: the deduced amino-acid sequence, which reveals that it is a G protein-coupled receptor; the tissue distribution of its messenger RNA, which is compatible with that of the D1 dopamine receptor; its pharmacological profile when transfected into COS-7 cells; and its ability to stimulate the accumulation of cyclic AMP in human 293 cells.
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PMID:Cloning and expression of human and rat D1 dopamine receptors. 216 20

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.
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PMID:Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia? 1088 23

A substitution of phenylalanine by cysteine in position 124 is the only known naturally occurring variant of the human 5-HT1B (h5-HT1B) receptor. The present study was designed to evaluate the potential influence of the Cys-124 variant on pharmacological properties of the receptor and to test for an involvement of the mutation in the genetic predisposition to schizophrenia or bipolar affective disorder. Binding of [3H]5-carboxamidotryptamine ([3H]5-CT) and its competition with serotonin receptor agonists and antagonists were determined in COS-7 cells transfected with the wild-type or the variant h5-HT1B receptor cDNA. In saturation experiments with [3H]5-CT, the maximum binding (Bmax) of the variant receptor was approximately 30% of the wild-type receptor. In competition experiments with 1 nM [3H]5-CT, the following serotonin receptor ligands exhibited a two to three times higher affinity for the mutant than for the wild-type receptor: dihydroergotamine, L-694,247, SB-216641, 5-CT, 5-HT, sumatriptan, RU24969 and methysergide (compounds listed at decreasing order of potency at the wild-type receptor). In contrast, the serotonin receptor antagonist ketanserin exhibited higher binding affinity for the wild-type than for the mutant h5-HT1B receptor and GR127939, (-)propranolol and BRL-15572 showed equal affinity for both types of receptor. Mutation screening of schizophrenic and bipolar patients revealed no relationship between the variant receptor and development of disease. In conclusion, our data suggest that the Cys-124 variant significantly affects the pharmacological properties of the h5-HT1B receptor. Carriers of the variant may exhibit differences in response to drugs acting on the h5-HT1B receptor or may develop side-effects to such agents.
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PMID:Modified ligand binding to the naturally occurring Cys-124 variant of the human serotonin 5-HT1B receptor. 1020 48

This study reports on the long-term course of 11 patients (6 girls, 5 boys) with childhood onset schizophrenia (COS, age at onset < 10 years). Patients were examined twice (mean follow-up period 38 years after onset). The premorbid development is assessed in terms of the Modified Premorbid Adjustment Scale (M-PAS) and additionally described by distinct psychopathological categories. The psychopathology at the onset of psychosis and at the second follow-up examination was assessed by categorical application of the Positive and Negative Syndrome Scale (PANSS). The outcome was rated with the Disability Assessment Score (DAS). The course of psychotic episodes and intervals between them is presented according to DSM-IV subtype classifications. Ten of 11 patients presented premorbid developmental peculiarities that were not adequately covered by the M-PAS subscales. Whereas in the 4 patients with acute onset of psychosis the positive PANSS-type was predominant, in the 7 patients with an insidious onset the negative PANSS-type prevailed. The nature of the diagnostic subtypes varied markedly across the course of the illness. In case of a continuous predominant catatonic symptomatology the outcome was poor. Detailed case descriptions help to illuminate the heterogeneous psychopathology of COS. Various temporary premorbid behavioral peculiarities were precursors of COS. A differentiation between premorbid and prodromal signs proved to be arbitrary. Our results contradict the assumption that COS is characterized only by a negative symptomatology.
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PMID:Schizophrenia with onset before the age of eleven: clinical characteristics of onset and course. 1081 18

Atypical antipsychotic drugs, which are distinguished from typical antipsychotic drugs by a lower incidence of extra-pyramidal side effects and less propensity to elevate serum prolactin levels (e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone), have become the most widely used treatments for schizophrenia, although their precise mechanism of action remains controversial. It has been suggested that this group of atypical antipsychotic drugs is characterized by preferentially high affinities for 5-hydroxytryptamine (5-HT)2A serotonin receptors and relatively low affinities for D2-dopamine receptors. It has recently been proposed that these atypical antipsychotic drugs may also be distinguished from typical antipsychotic drugs (e.g., haloperidol, fluphenazine, chlorpromazine, and so on) by inverse agonist actions at the 5-HT2C-INI RNA edited isoform of the human 5-HT2C receptor transiently expressed in COS-7 cells. We have examined the relationship among 5-HT2C inverse agonist potency, efficacy, and atypical antipsychotic drug status in HEK-293 cells of a large number of typical and atypical antipsychotic drugs using human embryonic kidney (HEK)-293 cells stably transfected with the h5-HT2C-INI receptor. Inverse agonist actions at h5-HT2C-INI receptors were measured for both typical and atypical antipsychotic drugs. Thus, some typical antipsychotic drugs (chlorpromazine, mesoridazine, fluphenazine, and loxapine) were efficient inverse agonists, whereas several clinically effective atypical antipsychotic drugs (remoxapride, quetiapine, sulpiride, melperone, amperozide) were not. Additionally, several drugs without significant antipsychotic actions (M100907, ketanserin, mianserin, ritanserin, and amitriptyline) were potent inverse agonists at the 5-HT2C-INI isoform expressed in HEK-293 cells. Taken together, these results demonstrate that both typical and atypical antipsychotic drugs may exhibit inverse agonist effects at the 5-HT2C-INI isoform of the human 5-HT2C receptor and that no relationship exists between inverse agonist actions and atypicality.
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PMID:Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor. 1156 Oct 66

Several independent studies have identified Disrupted In Schizophrenia 1 (DISC1) as a potential susceptibility factor in the pathogenesis of schizophrenia and severe recurrent major depression. To identify potential mechanisms by which DISC1 may influence development of psychiatric illness, we investigated the cellular consequences of recombinant DISC1 expression in COS-7 cells. We show that the N-terminal head domain is sufficient for DISC1 mitochondrial and nuclear targeting, while sequence from the C-terminus facilitates centrosomal association. Loss of C-terminal sequence alters DISC1 subcellular distribution, significantly increasing nuclear localization. DISC1 over-expression produces striking mitochondrial reorganization in some cells, with formation of mitochondrial ring-like structures, indicating a potential involvement of DISC1 in mitochondrial fusion and/or fission.
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PMID:Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. 1620 27

Childhood-onset schizophrenia (COS; defined as onset by age 12 years) is rare, difficult to diagnose, and represents a severe and chronic phenotype of the adult-onset illness. A study of childhood-onset psychoses has been ongoing at the National Institute of Mental Health (NIMH) since 1990, where children with COS and severe atypical psychoses (provisionally labeled "multidimensionally impaired" or MDI by the NIMH team) are studied prospectively along with all first-degree relatives. COS subjects have robust cortical gray matter (GM) loss during adolescence, which appears to be an exaggeration of the normal cortical GM developmental pattern and eventually mimics the pattern seen in adult-onset cases as the children become young adults. These cortical GM changes in COS are diagnostically specific and seemingly unrelated to the effects of medications. Furthermore, the cortical GM loss is also shared by healthy full siblings of COS probands suggesting a genetic influence on the abnormal brain development.
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PMID:Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia. 1790 36

D-amino-acid oxidase (DAO) is known to be associated with schizophrenia. Since the expression of DAO gene had been reported to be very low in LEA rats, we examined LEA/SENDAI rats in detail. These rats did not have DAO activity, enzyme protein or mRNA encoding this enzyme. Sequencing of the 5'-upstream region of the DAO gene revealed the deletion of one triplet in the 15 TAA repeats approximately 700-bp upstream of the transcription start point. A 1.3-kb upstream fragment containing the TAA repeats and the transcription start point was inserted into a reporter vector and was transfected into COS-1, NRK-52E and CCL-PK1 cells. Although the fragments containing 15 or 14 repeats had high promoter activity, the fragment containing 13 repeats had very weak activity. Electrophoretic mobility-shift assays showed that the nuclear extracts from COS-1 and COS-7 cells had proteins that bound to the oligonucleotides containing the TAA repeats. These results suggest that the TAA repeats are important for expression of the DAO gene. The LEA/SENDAI rats lacking DAO would be a useful tool for the investigations aimed at the elucidation of the relationships between this flavoenzyme and schizophrenia.
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PMID:Mutant rat strain lacking D-amino-acid oxidase. 1871 58

Childhood-onset schizophrenia (COS, age of onset between 7 and 14 years) is a rare and severe form of the disorder. The prevalence is about 1 / 50 of the rate of adult-onset schizophrenia. In COS-children emotional, cognitive and behavioural abnormalities are often seen years before illness onset. Premorbid symptoms including social withdrawal, isolation, introversion, peculiar behaviour, unmotivated temper tantrums, auto- and heteroaggressive acts, suicidal thoughts, anxiousness, paranoid ideas, represent early warning symptoms and are associated with an unfavourable outcome. About 60 % of 67 patients with COS examined by us (44 long-term-, 23 short-term-follow-up examinations) demonstrated premorbid abnormalities prior to the onset of their psychosis. We found a significant correlation between high M-PAS-scores, insidious onset, negative PANSS-Items, and early onset of age (< 12 years). High M-PAS-Scores were positively related to long duration of psychotic and residual states, and vice versa there was a negative correlation between M-PAS and a favourable outcome (long duration of recovery states). It is necessary to identify clinical states of elevated risk for psychosis as early as possible. This is difficult especially in young patients, in whom psychical peculiarities are ambiguous, and they may develop in different directions, most of them into normalization. Nevertheless, it is important to recognize risk-groups by time and to study their development carefully. Thus they could benefit from multiprofessional family-oriented early interventions.
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PMID:[Early development of childhood-onset schizophrenia]. 1982 Dec 19


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