Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian cells in culture have been used to study the genetic effects of physical and chemical agents. We have used Chinese hamster ovary (CHO) cells, clone K1-BH4, to quantify mutations at the X-linked, large (35 kb) hypoxanthine-guanine phosphoribosyltransferase (hprt) locus (the CHO/HPRT assay) induced by environmental agents. By transfecting an hprt-deletion mutant CHO cell line with the plasmid vector pSV2gpt, we isolated a transformant, AS52. AS52 cells carry a single functional copy of an autosomal, small (456 bp) xanthine-guanine phosphoribosyltransferase (gpt) gene (the bacterial equivalent of the mammalian hprt gene; AS52/GPT assay). We found that ionizing radiations such as X-rays and neutrons and oxidative genotoxic chemicals such as Adriamycin, bleomycin, hydrogen peroxide, and potassium superoxide are much more mutagenic to the gpt gene in AS52 cells than to the hprt locus in K1-BH4 cells. The hypermutability of the gpt gene probably results from a higher recovery of multilocus deletion mutants in AS52 cells than in K1-BH4 cells, rather than a higher yield of induced mutants. These results demonstrate that the use of the hprt locus alone could lead to an underestimate of the genetic risk of these agents. Analyses of the mutation spectrum using a polymerase chain reaction-based deletion screening and DNA sequencing procedure showed that a high proportion of HPRT- and GPT- mutants induced by X-rays carry deletion mutations. Thus, both the mutant frequency and mutation spectrum need to be considered in assessing the genetic risk of ionizing radiation and oxidative genotoxic chemicals.
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PMID:Quantitative and molecular analyses of genetic risk: a study with ionizing radiation. 814 20

The goal of this study was to determine the developmental pattern of expression of the X-linked gene for hypoxanthine phosphoribosyltransferase (Hprt) during spermatogenesis and the relevance of this expression to X-chromosome inactivation during meiotic prophase. The results demonstrated that HPRT activity is maintained in mouse spermatogenic cells throughout development in spite of X-chromosome inactivation; however, specific activities of HPRT in meiotic and postmeiotic germ cells were significantly lower than in premeiotic ones. Maintenance of Hprt transcripts at all stages was also demonstrated. Interestingly, the highest level of Hprt transcripts was found in leptotene/zygotene spermatocytes, suggesting a hyperactivation of the Hprt gene and/or stabilization of Hprt transcripts in these cells. Hprt transcripts were present at very low levels in pachytene spermatocytes, and at slightly elevated levels in round spermatids. It was also found that the relative abundance of Hprt transcripts in the somatic cells of germ-cell-deficient testes was much greater than that in meiotic and postmeiotic germ cells, even though their activities of HPRT were similar. Examination of the translational status of Hprt transcripts in testicular cells revealed that while most of the transcript was translationally active in somatic cells of testes, less than half of the transcript was on polysomes in pachytene spermatocytes and round spermatids. Since no functional autosomal Hprt gene exists in the mouse, these data suggest that the germ cell maintains both transcript and protein product of the Hprt gene in spite of apparent X-chromosome inactivation.
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PMID:Expression of the Hprt gene during spermatogenesis: implications for sex-chromosome inactivation. 821 41

Using a variety of genetic methods, it is shown in this paper that the genes GLA, G6PD, HPRT, and PGK are X-linked in the vole Microtus subarvalis. The order of these genes has been investigated in two vole species, M. subarvalis and M. kirgisorum, by using the mapping technique of Goss and Harris (1977a, b), which depends on the analysis of gamma-ray-induced gene segregation. The experimental data were processed with the computer programme RHMAP (Ginsburg et al., 1993). The analysis indicated that the correct gene order in M. subarvalis is PGK-HPRT-G6PD-GLA, and the same gene order was found to be the most probable for M. kirgisorum. The relative distances between the genes in the two vole species are apparently the same. The RHMAP programme has also been applied to data previously reported for the same set of X-linked genes in the American mink (Zhdanova et al., 1988), the Australian marsupial Planigale maculata (Dobrovic and Graves, 1986), and man. The evolutionary conservation of the linear order of these X-linked genes in different mammalian taxa is discussed.
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PMID:Demonstration of the X-linkage and order to the genes GLA, G6PD, HPRT, and PGK in two vole species of the genus Microtus. 825 99

Fragile X syndrome is the most common form of inherited mental retardation in man. The disease is associated with expansion in the number of tandem CGG trinucleotide repeats in the 5' untranslated region of the human FMR1 gene. Transmitting males, individuals who are unaffected carriers of the disease, show a moderate increase in the number of repeat units, while fully penetrant males show a major expansion in repeat number. Major expansion of the repeat in affected males is correlated with methylation of certain restriction enzyme recognition sites in the 5' CpG island containing the trinucleotide repeat in these patients. Phenotypic expression of the mutation appears to be due to transcriptional silencing of the FMR1 gene. We now report direct high resolution methylation analysis of the trinucleotide repeat and its flanking regions using ligation-mediated PCR genomic sequencing. We find the cytosine residue of all CpG dinucleotides examined within and surrounding the FMR1 trinucleotide repeat to be unmethylated in the DNA of normal male leukocytes and transmitting male lymphoblasts; these same cytosines are methylated in affected male lymphoblasts, in a somatic cell hybrid containing a fragile X chromosome from an affected male, and in a somatic cell hybrid containing a normal inactive X chromosome. The methylation pattern of the FMR1 5' CpG island in affected patients as determined by genomic sequencing is remarkably similar to that seen for the X-linked human phosphoglycerate kinase and hypoxanthine phosphoribosyltransferase gene 5' CpG islands on the inactive human X chromosome.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome. 826 19

DNA methylation within GC-rich promoters of constitutively expressed X-linked genes is correlated with transcriptional silencing on the inactive X chromosome in female mammals. For most X-linked genes, X chromosome inactivation results in transcriptionally active and inactive alleles occupying each female nucleus. To examine mechanisms responsible for maintaining this unique system of differential gene expression, we have analyzed the methylation of individual cytosine residues in the 5' CpG island of the human hypoxanthine phosphoribosyltransferase (HPRT) gene on the active and inactive X chromosomes. Methylation analysis of 142 CpG dinucleotides by genomic sequencing was carried out on purified DNA using the cytosine-specific Maxam and Gilbert DNA sequencing reaction in conjunction with ligation-mediated PCR. These studies demonstrate the 5' CpG islands of active and 5-azacytidine-reactivated alleles are essentially unmethylated while the inactive allele is hypermethylated. The inactive allele is completely methylated at nearly all CpG dinucleotides except in a 68-bp region containing four adjacent GC boxes where most CpG dinucleotides are either unmethylated or partially methylated. Curiously, these GC boxes exhibit in vivo footprints only on the active X chromosome, not on the inactive X. The methylation pattern of the inactive HPRT gene is strikingly different from that reported for the inactive X-linked human phosphoglycerate kinase gene which exhibits methylation at all CpG sites in the 5' CpG island. These results suggest that the position of methylated CpG dinucleotides, the density of methylated CpGs, the length of methylated regions, and/or chromatin structure associated with methylated DNA may have a role in repressing the activity of housekeeping promoters on the inactive X chromosome. The pattern of DNA methylation on the inactive human HPRT gene may also provide insight into the process of inactivating the gene early in female embryogenesis.
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PMID:High-resolution methylation analysis of the human hypoxanthine phosphoribosyltransferase gene 5' region on the active and inactive X chromosomes: correlation with binding sites for transcription factors. 828 17

Localization of genes GALA, G6PD, HPRT and PGK on X-chromosome of Microtus subarvalis has been proved. Using the radiation hybrid mapping technique of Goss and Harris, the order of these genes for two species M. subarvalis and M. Kirgisorum was established. Statistical methods (program package RHMAP) result in the only gene order PKG--HPRT--G6PD--GALA for M. subarvalis. The same order was found to be the most probable for M. kirgisorum. Relative distances between these genes in two species appeared to be practically equal. A conservatism of a linear order of the X-linked genes in various mammalian taxons is discussed.
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PMID:[Establishment of linkage and the order of the genes GALA, G6PD, HPRT and PGK on the X-chromosome in two species of voles of the genus Microtus]. 830 70

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.
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PMID:Gout, uric acid and purine metabolism in paediatric nephrology. 843 71

We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister's for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS.
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PMID:Two sisters with clinical diagnosis of Wiskott-Aldrich syndrome: is the condition in the family autosomal recessive? 912 30

X-linked mutant alleles associated with prenatal male lethality are difficult to analyze because only heterozygous females are readily available for study. Genomic analysis of the mutant allele is facilitated by the construction of somatic cell hybrids because this enables the segregation of the X Chromosomes (Chrs) that carry the mutant and wild-type alleles. We describe here a method that ensures that the X Chr carrying the mutant allele is retained in somatic cell hybrids in an active selectable state. This is achieved by mating heterozygous females to males that carry a mutation at the hypoxanthine phosphoribosyl transferase (Hprt) locus. The resultant F1 females are compound heterozygotes, and when cells from these females are fused to HPRT- Chinese hamster cells and subjected to selection in HAT medium, the only survivors are those hybrid cells that retain an active X Chr carrying the mutant allele together with the wild-type Hprt allele. We use hybrids constructed by this method to demonstrate that there are no gross deletions or genomic rearrangements present in three mottled alleles associated with prenatal male lethality.
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PMID:The use of compound heterozygotes and Hprt selection to analyze X-linked mottled alleles associated with prenatal lethality. 867 24

We describe a general way of introducing transgenes into the mouse germ line for comparing different sequences without the complications of variation in copy number and insertion site. The method uses homologous recombination in embryonic stem (ES) cells to generate mice having a single copy of a transgene integrated into a chosen location in the genome. To test the method, a single copy murine bcl-2 cDNA driven by either a chicken beta-actin promoter or a human beta-actin promoter has been inserted immediately 5' to the X-linked hypoxanthine phosphoribosyltransferase locus by a directly selectable homologous recombination event. The level of expression of the targeted bcl-2 transgene in ES cells is identical in independently isolated homologous recombinants having the same promoter yet varies between the different promoters. In contrast, the expression of bcl-2 transgenes having the same (chicken beta-actin) promoter varies drastically when they are independently integrated at random insertion sites. Both promoters direct broad expression of the single-copy transgene in mice derived from the respective targeted ES cells. In vitro and in vivo, the human beta-actin promoter consistently directed a higher level of transgene expression than the chicken beta-actin promoter.
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PMID:Single-copy transgenic mice with chosen-site integration. 879 6


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