Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2-c] pyrazolo[3,4-e]-pyrimidine) is a novel agent that is chemically unrelated to available antipsychotics and is not a dopamine receptor antagonist. Like available antipsychotics, CI-943 reduces spontaneous locomotion in mice and rats and inhibits compulsive cage climbing induced by apomorphine in mice at doses that do not produce ataxia. However, CI-943 enhances rather than inhibits the locomotor stimulant effects of d-amphetamine in mice and rats. Unlike dopamine antagonists, CI-943 does not affect stereotypy caused by apomorphine or amphetamine in rats. CI-943 displays an antipsychotic-like profile in conditioned avoidance tests, inhibiting one-way avoidance in rats at doses that do not impair escape and inhibiting continuous avoidance in rats and squirrel monkeys at doses that do not impair shock termination responding. Although high doses of CI-943 produce dystonic movements in haloperidol-sensitized monkeys, CI-943 differs from dopamine antagonists that produce extrapyramidal dysfunction in humans in that doses of CI-943 that are sufficient to inhibit avoidance responding in monkeys do not produce extrapyramidal dysfunction. Unlike dopamine antagonists that produce tardive dyskinesia, CI-943 administered repeatedly at high doses does not produce behavioral supersensitivity to dopamine agonists in rats. These results demonstrate that CI-943 resembles available antipsychotics in some preclinical behavioral tests commonly used to predict antipsychotic efficacy but differs from dopamine antagonists in tests predictive of dopamine receptor antagonism and antipsychotic-induced neurological dysfunction.
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PMID:CI-943, a potential antipsychotic agent. I. Preclinical behavioral effects. 257 12

We describe two previously unrecognized splice site mutations of GCH1 in Dopa responsive dystonia (DRD). Both mutations affect consensus splice acceptor (AG) sites. The first mutation is an A-->G transition at position -2 of intron 1 of GCH1. This mutation results in skipping of exon 2. Fusion of exons 1 and 3 causes a frame shift that generates a premature stop codon. The second mutation is an A-->G transition at position -2 of intron 2. The mutation generates a new splice acceptor site AG one base pair upstream of the wild-type splice site. This, together with a pyrimidine stretch upstream of the new splice site, renders this site functional and generates a transcript with the insertion of one base, i.e. the G of the wild-type splice site. This in turn causes a frame shift including the introduction of a premature stop codon. The two different mutations generate truncated GTP cyclohydrolase polypeptides.
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PMID:Two previously unrecognized splicing mutations of GCH1 in Dopa-responsive dystonia: exon skipping and one base insertion. 1073 14

Lesch-Nyhan disease (LND) is a rare disorder caused by a defect of an enzyme in the purine salvage pathway, hypoxanthine phosphoribosyl transferase (HPRT). It is still unknown how the metabolic defect translates into the complex neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in purine and pyrimidine nucleotide content in HPRT-deficient cells. We hypothesized that altered nucleotide concentrations in HPRT deficiency change G-protein-mediated signal transduction. Therefore, our original study aim was to examine the high-affinity GTPase activity of G-proteins in membranes from primary human skin and immortalized mouse skin fibroblasts, rat B103 neuroblastoma cells and mouse Neuro-2a neuroblastoma cells. Unexpectedly, in membranes from human fibroblasts, B103- and Neuro-2a cells, V(max) of low-affinity nucleoside 5'-triphosphatase (NTPase) activities was decreased up to 7-fold in HPRT deficiency. In contrast, in membranes from mouse fibroblasts, HPRT deficiency increased NTPase activity up to 4-fold. The various systems analyzed differed from each other in terms of K(m) values for NTPs, absolute V(max) values and K(i) values for nucleoside 5'-[beta,gamma-imido]triphosphates. Our data show that altered membrane NTPase activity is a biochemical hallmark of HPRT deficiency, but species and cell-type differences have to be considered. Thus, future studies on biochemical changes in LND should be conducted in parallel in several HPRT-deficient systems.
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PMID:Altered membrane NTPase activity in Lesch-Nyhan disease fibroblasts: comparison with HPRT knockout mice and HPRT-deficient cell lines. 1593 74