Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lesch-Nyhan syndrome is characterized by a deficiency of the enzyme hypoxanthine phosphoribosyl transferase (HPRT), compulsive self-mutilatory behavior (SMB), and a loss of central dopaminergic neurons. In order to model the loss of central dopamine-containing neurons in this developmental disorder, neonatal rat pups 3 days of age were given the neurotoxin 6-OHDA intracisternally to reduce brain dopamine. Accompanying the profound loss of dopamine produced by this treatment was an increase in striatal serotonin content. When these neonatally lesioned rats were challenged as adults with systemically administered L-DOPA or with muscimol administration into substantia nigra reticulata (SNR), SMB was observed, a response not observed in unlesioned rats. Thus, the neonatally lesioned rats exhibit increased susceptibility for SMB. Since a D1-dopamine antagonist blocked the SMB response to L-DOPA, it was proposed that D1-dopamine receptors were critical to this behavioral response. Basic investigations concerning D1-dopamine receptor mechanisms in the lesioned rats have been performed and these are reviewed. The data in the neonatally lesioned rats provide convincing evidence that the absence of central dopaminergic neurons is responsible for at least some of the neurological symptoms of the Lesch-Nyhan syndrome, a finding consistent with data collected in mice with an HPRT deficiency.
Brain Res Bull 1990 Sep
PMID:A dopamine deficiency model of Lesch-Nyhan disease--the neonatal-6-OHDA-lesioned rat. 212 38

The hprt (hypoxanthine guanine phosphoribosyltransferase) T cell cloning assay was used to detect in vivo mutations in T lymphocytes of individuals receiving radioimmunoglobulin therapy (RIT). A total of 28 patients receiving 131I and/or 90Y-labeled antiferritin antibodies was studied. Mutant frequencies for patients were clearly much higher than for historic non-treated controls (median 68.0 X 10(-6) for patients versus a median of 6.8 X 10(-6) for 115 controls). There was a good correlation of mutant frequency with initial activity of RIT (rlinear = 0.68, rquadratic = 0.76; P less than 0.05) although the correlation of mutant frequency with total activity after several rounds of treatment was poor (R = 0.18). Molecular studies of the hprt mutants demonstrated that a much higher proportion of mutations occurring in RIT treated patients had gross structural alterations of the hprt gene (33%) than did mutations occurring in controls (15%). There was a good correlation (r = 0.72) of mutants with gross alterations and total RIT activity. T cell receptor gene studies demonstrated that most of the mutants (92%) represented independent in vivo mutations, which is similar to previous findings with background mutations in non-irradiated individuals. These studies demonstrate the usefulness of the hprt T cell cloning assay for studies of in vivo human somatic cell gene mutations resulting from ionizing radiation.
Mutagenesis 1990 Sep
PMID:Molecular analysis of in vivo hprt mutations in human T lymphocytes. V. Effects of total body irradiation secondary to radioimmunoglobulin therapy (RIT) 217 31

Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of [13C]leucine and, in Lesch-Nyhan subjects, [2H5]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 mumol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 mumol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, [13C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With [13C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 +/- 0.74 (SD) and catabolism 4.85 +/- 0.57 (g/kg/24 h, n = 5). Similar results were obtained in Lesch-Nyhan subjects using [2H5]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Pediatr Res 1990 Sep
PMID:Protein metabolism in phenylketonuria and Lesch-Nyhan syndrome. 223 21

Alterations in the hprt gene of Chinese hamster cells were determined in 71 spontaneous, methylmethane sulphonate (MMS)- and X-ray-induced mutants, using the Southern blot hybridization technique. Among 41 MMS-induced mutants, deletions eliminating the whole gene were observed in 17 cases (41%). Analysis of 20 X-ray-induced mutants revealed the presence of similar deletions in nine of them (45%). No evidence of deletion was found in 10 spontaneous mutants. To investigate the possibility of small deletions, 18 MMS-induced mutants were studied with probes derived from exons 3 and 9 but no evidence of specific deletion of these two exons was found. The polymerase chain reaction (PCR) was used to phenotype hprt transcripts in 48 MMS, X-ray and spontaneous Chinese hamster mutants by amplifying the coding region of their cDNA. Among 22 MMS-induced mutants the message was present in 16 instances; 11 had normal levels while three had much lower levels of transcription. A further two mutants had mRNA of reduced size as revealed by the use of primers for PCR 3' to those routinely used. An analysis of 20 X-ray-induced mutants showed the presence of hprt mRNA in 11 of them with five having low levels of transcription. Among six spontaneous mutants, four were negative for mRNA on standard Northern blots and in one the message was only detected after PCR amplification. Direct DNA sequencing of 10 mutants revealed the presence of base substitutions in five of them while a 7 bp deletion was found in another. No mutations were found in another four mutants, suggesting the presence of mutation outside the coding region.
Mutagenesis 1990 Sep
PMID:Methylmethane-sulphonate and X-ray-induced mutations in the Chinese hamster hprt gene: mRNA phenotyping using polymerase chain reactions. 226 7

We have determined the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (hprt) mutations that arose in vivo in the T lymphocytes of a normal male subject. In previous studies approximately 16% (23/141) of the mutants from this individual analyzed by Southern blot displayed large structural alterations in hprt. Thirty-two mutants without these large hprt structural alterations produced sufficient hprt cDNA for polymerase chain reaction amplification and DNA sequence analysis. Base substitutions in hprt cDNA resulting in missense mutations and one mRNA splicing aberration (inclusion of intron sequences) were observed in 18/32 of these these mutants; substitutions occurred at both AT and GC base pairs. Small deletions (3/32), a tandem change and a single base insertion were also observed among the hprt cDNAs. Exon skipping and inclusion of hprt intron sequences in the hprt cDNA were observed in an additional 9/32 of the mutants. Analysis of T cell receptor (TCR) gene rearrangements revealed that six of eight mutants with an identical hprt T----A transversion displayed the same TCR rearrangement pattern, indicating that they were clonally related and arose from a single in vivo mutational event.
Mutagenesis 1990 Sep
PMID:DNA sequence analysis of in vivo hprt mutation in human T lymphocytes. 226 8

In humans, deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) is associated with a disorder known as Lesch-Nyhan syndrome which includes severe neurobehavioral abnormalities. Several animal models which have been developed to examine the neurobiologic substrates of this disorder have suggested a role for abnormal function in purine/dopamine neurotransmission, but the relationship between HPRT-deficiency and these abnormalities remains unknown. Recently, HPRT-deficient mice have been produced which appear to have similar, though more subtle changes in brain dopamine function. These mice will be useful in elucidating the relationship between HPRT-deficiency and the neurological deficits observed in patients with this disorder.
Brain Res Bull 1990 Sep
PMID:Animal models of Lesch-Nyhan syndrome. 229 45

In mammals, X-chromosome dosage compensation is achieved by inactivating one X chromosome in female cells. To test the hypothesis that genes on the silent X chromosome reactivate as a consequence of ageing, we examined the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 41 women who are heterozygous for mutations at this locus, leading to severe deficiency of the enzyme (Lesch-Nyhan syndrome). We find that heterozygotes who are more than 10 yr old have an excess of HPRT+ skin fibroblast clones (59% rather than the 50% expected as a consequence of random X inactivation) but this excess does not increase with age. Further studies of eight of these heterozygotes show that the silent locus does not detectably reactivate spontaneously in culture, but only in response to treatment with 5-aza-2-deoxycytidine, a potent inhibitor of methylation. There is no age difference in the frequency of this reactivation as assayed by HATr clones, and a more sensitive autoradiographic assay shows only a twofold difference between young and old heterozygotes. Thus, age-related reactivation is not a feature of all X-linked loci, and may have species, tissue and locus-specific determinants.
Nature 1988 Sep 01
PMID:Effect of ageing on reactivation of the human X-linked HPRT locus. 291 84

A variant clone of cultured chinese hamster lung fibroblasts (V79), selected for resistance to 8-azaguanine (V79 azagrst), although lacking hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), is able to convert hypoxanthine into IMP via purine-nucleoside phosphorylase (EC 2.4.2.1) and nucleoside kinase. In addition to the phosphoribosylation pathway, we also present evidence for the occurrence of a kinase-mediated pathway of recovery of hypoxanthine in the wild-type cells. The lower rate of formation of IMP in the V79 azagrst cells, apparently correlated with the phosphorylation of the nucleoside, suggests possible differences in the catalytic and/or regulatory properties of nucleoside kinase in the two cell lines. This fact might be of particular relevance in evaluating the mechanisms of resistance to purine analogs displayed by several cell types.
Arch Biochem Biophys 1988 Sep
PMID:Alpha-5-phosphoribosyl-1-pyrophosphate-independent salvage of purines in cultured Chinese hamster lung fibroblasts. 245 98

The C86 line of female embryonal carcinoma cells contains one active and one inactive X chromosome. Following methylnitrosourea mutagenesis, a clone called C86AGM2 was isolated that carries a mutated hprt gene on the active X chromosome. This hprtm allele encodes an HPRT enzyme that has less than 1% normal enzyme activity, is thermolabile, and has an altered isoelectric point. Following treatment with drugs that demethylate DNA, the hprt+ gene from the inactive X chromosome in C86AGM2 cells became active as determined by the appearance of HPRT activity with the thermodenaturation and electrofocusing characteristics of the normal enzyme. No expression of this hprt+ gene occurred if C86AGM2 cells were induced to differentiate prior to DNA demethylation. Stable lines of C86AGM2 cells expressing both the hprtm and hprt+ genes did not inactivate either gene following differentiation.
Somat Cell Mol Genet 1989 Sep
PMID:Reactivation of hprt on the inactive X chromosome with DNA demethylating agents. 247 61

To establish monkey liver cell lines with a high susceptibility to hepatitis A virus (HAV), marmoset (Saguinus labiatus) liver cells were fused with Vero cells deficient in hypoxanthine-guanine phosphoribosyltransferase and the resulting hybrid cells were selected in HAT medium. Of four hybrid cell lines obtained (S. 1a/Ve-1 to -4), three (S. 1a/Ve-1, -3 and -4) were equally susceptible to HAV infection. When inoculated with a virus isolated from marmoset liver tissue (10% liver tissue extract) or a faecal virus (10% stool extract) from a human hepatitis A patient, all susceptible cell lines showed a significant elevation of viral antigen activity as seen in radioimmunoassay and/or immunofluorescent antibody assays, at 4 to 6 weeks post-infection (p.i.) with the liver-derived inoculum and at 6 to 8 weeks p.i. with the stool-derived inoculum. In S. 1a/Ve-1 cells, a representative of the susceptible hybrid cell lines, full adaptation of HAV (liver tissue virus concentrate) to cell culture was attained after four serial passages. Thereafter, the virus grew to a plateau titre of 10(8.5) TCID50/ml at 7 days p.i. in a growth experiment. The infected cells showed no cytopathic effects but eventually a persistent infection was established when a saturated level of virus growth was reached.
J Gen Virol 1989 Sep
PMID:Propagation of hepatitis A virus in hybrid cell lines derived from marmoset liver and Vero cells. 255 May 76


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