Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The mutagenicity of two wild (Lactarius deliciosus and Boletus luteus) and two cultivated (Agaricus bisporus and Pleurotus ostreatus) mushrooms, preserved by canning and widely consumed in Spain, was studied in the Ames Salmonella/microsome test and in the CHO/HPRT assay system using mammalian cells. The mushroom extracts did not show mutagenicity in the microbial Ames test nor in the mammalian CHO-K1 cells, and this response was not modified by the presence of S-9 mix in the assay mixtures. Only the extracts from P. ostreatus showed a weak mutagenic activity in the CHO/HPRT assay in the presence of a metabolic activation system (S-9).
Food Chem Toxicol 1990 Sep
PMID:A study of the mutagenicity of some commercially canned Spanish mushrooms. 227 57

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

Lonidiamine is a novel indazole-carboxylic acid with antitumour properties; it has been studied for potential mutagenicity in a comprehensive battery of tests. In assays for the induction of gene mutations in prokaryotes (Ames test) and eukaryotes (induction of HPRT mutations in CHO cells), negative results were obtained. There was no evidence of the induction of chromosomal damage in cultured mammalian cells in vitro. No mutagenic activity was observed in tests for chromosomal damage in vivo, in somatic cells (micronucleus test) or in germinal cells (dominant lethal test). These negative results are consistent with observations indicating that lonidamine affects cellular energy processes, rather than the mechanisms of cell division. The lack of mutagenic properties suggests that lonidamine may present significant advantages in treatment of some tumours, offering a reduced risk of resistant clones, secondary cancer and heritable genetic damage.
Carcinogenesis 1990 Sep
PMID:Lonidamine: a non-mutagenic antitumor agent. 240 Oct 42

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

Recent reports by several laboratories indicate that not all non-essential target loci are equally capable of detecting chromosomal mutations. The present study was undertaken to determine if both the tk locus in mouse lymphoma cells and the hgprt locus in Chinese hamster ovary (CHO) cells can be used to quantitate chromosomal mutations. Seven known mutagens for the tk locus were selected. These compounds were evaluated in the mouse lymphoma assay and in a suspension adapted CHO assay for their mutagenicity. In addition to the specific locus mutagenesis analysis, mouse lymphoma and CHO cells were evaluated for the frequency of gross chromosome aberrations. From these investigations, it appears that only those compounds [2-methoxy-6-chloro-9-(3-[ethyl-2-chloroethyl] aminopropylamino)-acridine-dihydrochloride (ICR 170), ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS)] that induce significant numbers of large-colony thymidine kinase (TK) mutants also induce significant numbers of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) mutants. The four acrylates evaluated (methyl acrylate, ethyl acrylate, trimethylolpropane triacrylate and tetraethyleneglycol diacrylate) induced almost exclusively small-colony TK mutants and very few if any HGPRT mutants. Aberration analysis revealed that both the mouse lymphoma and CHO cells responded to the clastogenicity of the compounds (except for ICR 170 which was not positive in CHO cells) and that neither cell line was clearly more sensitive than the other to the clastogens tested. It is significant that the four acrylates give little or no evidence of genotoxicity when evaluated using selection for HGPRT-deficient mutants, yet are clearly clastogenic to the same cells in the same experiment. These results are consistent with the hypothesis that the hgprt locus may not be useful as a marker to evaluate the clastogenic component of a genotoxic compound. The present study adds to the increasing number of studies that support the view that the hemizygous nature of the hgprt locus permits the recovery of mutations primarily affecting the function of a single gene; whereas the heterozygous nature of the tk locus permits the recovery of both single gene and chromosomal mutations.
Mutagenesis 1989 Sep
PMID:Differential mutant quantitation at the mouse lymphoma tk and CHO hgprt loci. 268 35

We report the identification of a female patient with the X-linked recessive Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase [HPRT] deficiency). Cytogenetic and carrier studies revealed structurally normal chromosomes for this patient and her parents and demonstrated that this mutation arose through a de novo gametic event. Comparison of this patient's DNA with the DNA of her parents revealed that a microdeletion, which occurred within a maternal gamete and involved the entire HPRT gene, was partially responsible for the disease in this patient. Somatic cell hybrids, generated to separate maternal and paternal X chromosomes, showed that expression of two additional X-linked enzymes, phosphoglycerate kinase and glucose-6-phosphate dehydrogenase, were expressed only in cells that contained the maternal X chromosome, suggesting the presence of a functionally inactive paternal X chromosome. Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation revealed differences between DNA from the father and the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient. Together these data indicate that nonrandom inactivation of the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome were responsible for the absence of HPRT in this patient.
J Clin Invest 1989 Sep
PMID:Molecular analysis of a female Lesch-Nyhan patient. 276 Feb 9


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