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)

To determine whether mutations in the D5 dopamine receptor gene (DRD5) are associated with schizophrenia, the gene was examined in 78 unrelated schizophrenic individuals (156 DRD5 alleles). After amplification by the polymerase chain reaction, products were examined by dideoxy fingerprinting (ddF), a screening method related to single strand conformational polymorphism analysis that detects essentially 100% of mutations. All samples with abnormal ddF patterns were sequenced. Nine different sequence changes were identified. Five of these were sequence changes that would result in protein alterations; of these, one was a nonsense change (C335X), one was a missense change in an amino acid conserved in all dopamine receptors (N351D), two were missense changes in amino acids that are identical in only some dopamine receptors and in only some species (A269V; S453C), and one was a missense change in a non-conserved amino acid (P330Q). To investigate whether the nonsense change (C335X), predicted to prematurely truncate the receptor protein and result in a 50% diminution of functional protein, was associated with schizophrenia, other neuropsychiatric diseases, or specific neuropsychological, psychophysiological, or personality traits, both case-control and family analyses were performed. No statistically-significant associations were detected with schizophrenia or other neuropsychiatric disease. There also were no significant associations between any one measure of neuropsychological function. However, a post-hoc analysis of combined measures of frontal lobe function hinted that heterozygotes for C335X may have a vulnerability to mild impairment, but these findings must be interpreted with caution.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1995 Apr
PMID:The D5 dopamine receptor gene in schizophrenia: identification of a nonsense change and multiple missense changes but lack of association with disease. 763 97

We used the PCR amplification technique in an attempt to characterize further the dopamine D2L receptor expressed in the prolactin-secreting pituitary MMQ cell clone, derived from the prolactin- and ACTH-secreting Buffalo rat 7315 alpha pituitary tumour. By semiquantitative PCR amplification we were unable to detect the mRNA encoding the D2S receptor isoform, which derives from the well-known process of alternative splicing, producing two D2 receptor subtypes (D2L and D2S) in such tissues as the anterior pituitary and the corpus striatum. Although the pharmacology of the D2 receptor has been established in many studies on both native receptors and transfected receptor isoforms, because of the lack of tissues naturally expressing only one receptor isoform, MMQ cells represent the first example of cells uniquely or prevalently expressing only the D2L receptor, conceivably coupled to its native transduction mechanisms. These considerations prompted us to evaluate the pharmacology and the second messenger systems known to be modulated by dopamine. Scatchard analysis of [3H]spiperone binding resulted in a linear plot, consistent with the existence of a single class of binding sites, with a Kd of 0.055 +/- 0.002 nM and a Bmax of 27 +/- 3.5 fmol/mg protein. Competition experiments confirmed the GTP-dependence and the order of potency for agonist and antagonist ligands consistent with binding to a D2 receptor. The inhibitory effects of dopamine on adenylyl cyclase activity, inositol phosphate production and intracellular free calcium concentrations, the latter presumably via the opening of K+ channels, and prolactin secretion, as well as the reversal of the effect by the D2-selective antagonist (-)sulpiride and pretreatment with pertussis toxin, are consistent with the known biological actions of dopamine at D2 receptors. Based on our observations, the MMQ cell line can be considered a useful tool for investigating ligand-receptor interactions to develop new selective dopaminergic D2L ligands for the therapy of dopamine-related disorders such as schizophrenia, depression, Parkinson's disease and drug addiction.
J Mol Endocrinol 1995 Jun
PMID:Absence of D2S dopamine receptor in the prolactin-secreting MMQ pituitary clone: characterization of a wild D2L receptor coupled to native transduction mechanisms. 766 27

Studies on the molecular basis of neurological and psychiatric disorders often rely on the precise determination of specific proteins in brain tissues. In this study, we have developed a method for measuring the levels of the neural-specific growth-associated protein, GAP-43, in human postmortem brain specimens. This rapid and quantitative method is based on immunodetection procedures. Briefly, synaptosomal plasma membranes (SPMs) are deposited onto polyvinylidene difluoride (PVDF) membranes via a dot-blotting apparatus, followed by specific GAP-43 detection using a monospecific polyclonal antibody. Overall, the dot-blot procedure provided several advantages over Western blots and one-dimensional and two-dimensional polyacrylamide gels. The assays were more sensitive, reproducible, and allowed the rapid and simultaneous determination of multiple samples. Using this technique, we examined the levels of the GAP-43 protein in Brodmann's areas 17, 20, and 10 of schizophrenic and age-, sex-, and postmortem interval (PMI) matched controls. These studies revealed an increase in the levels of GAP-43 in visual association and frontal cortices (areas 20 and 10) of schizophrenic brains. Given the relationship of GAP-43 expression with the establishment and remodeling of neural connections, our results support the hypothesis that schizophrenia is associated with a perturbed organization of synaptic connections in associative areas of the human brain.
Mol Chem Neuropathol 1995 Jan
PMID:Increased levels of GAP-43 protein in schizophrenic brain tissues demonstrated by a novel immunodetection method. 775 43

We report a null mutation in the first exon of the human dopamine D4 receptor (DRD4) gene. The mutation is predicted to result in a truncated non-functional protein and is the first natural nonsense mutation found in a human dopamine receptor gene. It occurs with a frequency of about 2% in the general population. The distribution of the mutation was found to be similar in healthy controls and patients suffering from psychiatric diseases which included schizophrenia, bipolar affective disorder and Tourette's syndrome, indicating that heterozygosity for this mutation in the DRD4 gene is not causally related to major psychiatric diseases. We also identified an adult male who is homozygous for this mutation. He shows no symptoms of major psychiatric illness, but he displays somatic ailments including acousticous neurinoma, obesity and some disturbances of the autonomic nervous system. Some of these symptoms might be related to the absence of functional DRD4 protein.
Hum Mol Genet 1994 Dec
PMID:Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity. 788 21

The possibility that schizophrenia is associated with a differential expression, in the brain, of the short and long isoforms of the dopamine D2 receptor has been investigated by assessing the abundance of mRNA for each of the isoforms. Using a quantitative RNA-PCR technique, increased mRNA for both isoforms of the D2 receptor were observed in some brain regions, with no differential distribution between the isoforms in the schizophrenics compared to controls.
Brain Res Mol Brain Res 1994 Aug
PMID:The abundance of mRNA for dopamine D2 receptor isoforms in brain tissue from controls and schizophrenics. 798 46

Acute administration of the typical neuroleptic haloperidol (HAL, 2 mg/kg) induced the immediate-early gene proteins (IEGPs) c-Fos, Fos-related antigens (FRAs), FosB, JunB, JunD and Krox24 in the striatum and nucleus accumbens of the rat brain. In contrast, acute administration of the atypical antipsychotic drug clozapine (CLOZ, 30 mg/kg) induced only FRAs, JunB and Krox24 IEGPs in the striatum, and c-Fos, FRAs, and Krox24 IEGPs in the nucleus accumbens. c-Jun was not induced by acute administration of HAL or CLOZ in the rat brain. Differential induction of IEGs by HAL and CLOZ was also observed in the lateral septal nucleus and the islands of Calleja complex of the rat brain. These differences in IEG induction by HAL and CLOZ may be related to the different clinical profiles of the two drugs. Specifically, CLOZ induces FRAs in the islands of Calleja and lateral septum and this action may be involved in its therapeutic effects on the negative symptoms of schizophrenia, whereas HAL produces a coordinate induction of Fos and JunB in striatal neurons and this dimer combination may be involved in producing the extrapyramidal side-effects of typical neuroleptics.
Brain Res Mol Brain Res 1994 Apr
PMID:Clozapine and haloperidol produce a differential pattern of immediate early gene expression in rat caudate-putamen, nucleus accumbens, lateral septum and islands of Calleja. 802 80

An increase in the severity of schizophrenia through consecutive generations (anticipation) has been found in some studies of families with affected members. Anticipation in five neurological disorders is known to arise from the expansion of CAG repeats between generations of affected individuals. The 'repeat expansion detection' method was used to screen individual genomes for the size of such expansions in a sample of schizophrenic and normal subjects. Comparison of the frequency distribution of CAG expansions observed in schizophrenic patients to that for normal subjects, showed that there are significantly more expansions in patients (p = 0.048). When male and female subjects are considered separately, there is a highly significant difference in the distribution of repeat sizes found between affected and normal females (p = 0.0023) but no significant difference between affected and normal males. Overall there is a 28% excess of expansions observed in affected versus normal females, and their presence confers a relative risk of 4.12 (p < 0.005). In contrast, the frequency distribution of age-at-onset with respect to repeat size is nearly the same in male and female patients and, when the sexes are combined, the larger (CAG)69-136 expansions are associated with a younger age-at-onset (p = 0.02).
Hum Mol Genet 1995 Oct
PMID:CAG repeat expansions and schizophrenia: association with disease in females and with early age-at-onset. 859 21

Aromatic L-amino acid decarboxylase (AADC) has previously been shown to be up-regulated at the level of its protein activity and its mRNA abundance by antipsychotic drugs. Its activity has also been shown to be down-regulated by dopamine agonists including amphetamine. In this study we have injected rats for up to 32 days with amphetamine and the anti-epileptic drug vigabatrin, both of which can cause psychosis with similarities to schizophrenia. We have shown that AADC mRNA levels are reduced in most brain regions by both drugs. Cocaine and other non-psychotogenic anti-epileptic drugs had no effect in this paradigm. Two products of this enzyme are implicated in psychotogenesis.
Brain Res Mol Brain Res 1996 Jan
PMID:Amphetamine and vigabatrin down regulate aromatic L-amino acid decarboxylase mRNA levels. 871 41

The two most consistent features of the diseases caused by trinucleotide repeat expansion-neuropsychiatric symptoms and the phenomenon of genetic anticipation-may be present in forms of dementia, hereditary ataxia, Parkinsonism, bipolar affective disorder, schizophrenia and autism. To identify candidate genes for these disorders, we have screened human brain cDNA libraries for the presence of gene fragments containing polymorphic trinucleotide repeats. Here we report the cDNA cloning of CAGR1, originally detected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bp open reading frame encoding 359 amino acids. This amino acid sequence is homologous (56% amino acid identify and 81% amino acid conservation) to the Caenorhabditis elegans cell fate-determining protein mab-21. CAGR1 is expressed in several human tissues, most prominently in the cerebellum, as a message of approximately 3.0 kb. The gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are available to link the long repeat to this clinical phenotype, an expansion mutation of the CAGR1 repeat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.
Hum Mol Genet 1996 May
PMID:cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat. 873 27

1. Tardive dyskinesia is more important in postmenopausal women than men of comparable age and a peak of first episodes of schizophrenia is observed in postmenopausal women. The effect of ovariectomy (2 weeks or 3 months) in rats was investigated as a model of decreased gonadal function associated with menopause. 2. Frontal cortex D1 receptor density and affinity were similar in intact male compared to intact female rats and progressively decreased in density with time after ovariectomy, with no change of affinity. Striatal D1 and D2 receptors also decreased in density after ovariectomy for both receptor subtypes, with no change of affinity. Striatal D1 receptor density and affinity were similar in intact male and female rats, whereas the density of D2 receptors was higher in females. Treatment with estradiol for 2 weeks restored the D2 but not the D1 receptor changes. 3. In the substantia nigra pars reticulata, striatum, nucleus accumbens, and entopeduncular nucleus, a progressive increase in [3H]flunitrazepam specific binding associated with GABAA receptors was observed as a function of time following ovariectomy; this was corrected with estradiol treatment. In contrast, the opposite was observed for [3H] flunitrazepam binding in the globus pallidus, where ovariectomy decreased binding, which was corrected with estradiol replacement therapy. 4. Low prefrontal cortex dopamine activity with implications of D1 receptors in negative symptoms of schizophrenia is hypothesized. Furthermore, GABAergic overactivity in the internal globus pallidus-substantia nigra pars reticulata complex is hypothesized in tardive dyskinesia. 5. The present data suggest that gonadal hormone withdrawal by reducing brain dopamine receptors and producing an imbalance of GABAA receptors in the output pathways of the striatum may predispose to schizophrenia and dyskinesia.
Cell Mol Neurobiol 1996 Apr
PMID:The modulation of brain dopamine and GABAA receptors by estradiol: a clue for CNS changes occurring at menopause. 874 69


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