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)

Man-mouse and man-Syrian hamster somatic hybrid cell lines were prepared by fusion of mouse A9 or hamster TG2 cells, which are deficient in hypoxanthine-guanine phosphoribosyl transferase, with cells of a diploid fibroblastic strain, KOP-1, derived from a woman heterozygous for an X-autosome translocation. 61 clones were derived in nonselective medium and 85 sublines of these were derived in selective media: 53 in hypoxanthine-aminopterine-thymidine and 32 in 8-azaguanine. All three human X-linked markers studied, i.e., hypoxanthineguanine phosphoribosyl transferase (EC 2.4.2.8), glucose-6-phosphate dehydrogenase (EC 1.1.1.49), and phosphoglycerate kinase (EC 2.7.2.3), were present together, or absent together, in most of these clones and sublines. However, loss or retention of only phosphoglycerate kinase was occasionally observed, even in the absence of selective growth, while no evidence of separation of hypoxanthine-guanine phosphoribosyl transferase from glucose-6-phosphate dehydrogenase occurred. Cytological examination of eight man-hamster clonal lines by the quinacrine fluorescent technique showed that human phosphoglycerate kinase was only present when the translocation chromosome carrying most of the long arm of the X chromosome was present. The presence of human glucose-6-phosphate dehydrogenase and hypoxanthine-guanine phosphoribosyl transferase was not related to the presence or absence of this chromosome, but appeared to be correlated with the presence of the other translocation chromosome.
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PMID:Cytological mapping of human X-linked genes by use of somatic cell hybrids involving an X-autosome translocation (mouse-hamster-human X-linked markers). 450 May 56

For study of the basis of an X-linked form of gout in man, several clonal lines deficient in hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) were selected from the human lymphoblast line WI-L2 by spontaneous and mutagen-induced resistance to 10 muM 8-azaguanine. Three groups could be defined: (1) clones with less than 1% of normal enzyme activity, unable to incorporate [(3)H]hypoxanthine detectable by radioautography, unable to tuilize exogenous hypoxanthine as a source of purines, and showing a 2- to 4-fold accelerated rate of production of early intermediates in de novo purine biosynthesis; (2) clones with 56-63% of normal enzyme activity, decreased incorporation per cell of [(3)H]hypoxanthine measured by radioautography, able to utilize exogenous hypoxanthine, and showing 1.2- to 2.8-fold purine overproduction; (3) clones with 10-15% of normal enzyme activity, able to utilize hypoxanthine but not incorporating amounts detectable by radioautography, and showing a 2.3- to 2.5-fold increase in purine biosynthesis. Resistant clones generated by ICR 191 mutagenesis resembled Group 1 clones. Heat inactivation studies in crude extracts from certain clones in Group 2 suggest a structural gene mutation, but no qualitative alteration in enzyme could be detected by starch gel electrophoresis. These phenotypes have persisted over at least 300 generations of nonselective growth, with retention of a diploid karyotype.
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PMID:Expression of purine overproduction in a series of 8-azaguanine-resistant diploid human lymphoblast lines. 452

The activity of hypoxanthine-guanine phosphoribosyltransferase in unfertilized mouse ova and in mouse embryos at the two-cell stage is proportional to the number of X chromosomes present during oogenesis. This indicates that the enzyme is X-linked in the mouse and that inactivation of the X chromosome does not occur during oogenesis. However, the genetic dosage effect of the X chromosomes is not present after the increase in hypoxanthine-guanine phosphoribosyltransferase activity in the late morula and the blastocyst stages. These results indicate that the X-linked enzyme lacuts is expressed sometimne after fertilization but before the morula stage.
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PMID:Expression of the mammalian X chromosome before and after fertilization. 501 77

Humans with the Lesch-Nyhan syndrome have an X-chromosomal mutant gene that causes severe neurological and developmental abnormalities. The patients are deficient in hypoxanthine-guanine phosphoribosyltransferase, which converts hypoxanthine to inosinic acid, a major precursor of adenine and guanine nucleotides. Paradoxically, the enzyme defect causes hypernormal de novo synthesis of inosinic acid, which manifests itself as excesses of hypoxanthine, xanthine, and uric acid. The first step in the de novo pathway is thought to be rate-limiting, due to feedback repression by adenine and guanine nucleotides. The derepressed rate of purine production in mutants and their failure to thrive could result from reduction in the amounts of nucleotides derived from inosinic acid to levels that are inadequate for normal feedback control and for nucleic acid synthesis needed in growth. Studies with cultured cells, reported here, support the interpretation that mutants are, in effect, nucleotide-deficient. Skin fibroblasts from patients fail to proliferate in media that do not contain supplementary adenine or folic acid, a participant in two stages of purine biosynthesis. The folic acid requirement of mutant cells is at least 50-fold greater than that of normal cells, which can synthesize all the nucleotides needed for growth without exogenous adenine. Both folic acid and adenine supplements are thought to provide mutant cells with the means of making more inosinic acid available for conversion to adenine and guanine nucleotides. It is not clear why the availability of inosinate or its conversion to other nucleotides is impaired. Therapy with adenine or folic acid begun at the time of birth may avert development of the disease in mutant males.The relevant gene is X-linked and shows clonal, single-allele-expression: phenotypically normal and phenotypically mutant clones have been derived from females heterozygous for the mutant gene. The phenotypically mutant heterozygous clones have the same requirement for adenine or folic acid as cells from hemizygous mutant males, an indication that the normal allele is repressed in these clones. The adenine-folic acid requirement of mutant cells provides a method of direct, clonal selection for rare, phenotypically normal cells in mutant populations, which is applicable to the single-active-X problem and other in vitro genetic studies.
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PMID:Purine requirement of cells cultured from humans affected with Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase deficiency). 525 31

A hybrid cell line of clonal origin has been obtained by cocultivation of two biochemically marked human cell strains. One parental line is diploid and derived from a male infant with orotic aciduria, a rare autosomal recessive disease. This line has deficient activity for the final two enzymes in the biosynthetic pathway leading to uridylic acid and possesses the B electrophoretic type of glucose-6-phosphate dehydrogenase. The other parental line (D98/AH-2) is heteroploid, is resistant to 8-azahypoxanthine, and has deficient inosinic acid pyrophosphorylase activity. It displays the A(+) variant of glucose-6-phosphate dehydrogenase. The A(+) and B types of this dehydrogenase are known to be determined by allelic, sex-linked, Mendelian genes. The cloned hybrid cells exhibit genetic traits of both parents: (1) Their modal chromosome number is approximately the sum of those of the two parental lines; (2) they have levels of activity for both enzymes affected by the gene for orotic aciduria which are intermediate between those of the two parental lines; (3) they have higher activity than the D98/AH parent for inosinic acid pyrophosphorylase; (4) they have both A(+) and B isozyme bands of glucose-6-phosphate dehydrogenase. These hybrid cells represent the first known example of a cloned line of mammalian origin in which two X-linked allelic genes function.
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PMID:Hybridization of two biochemically marked human cell lines. 525 9

Cultured skin fibroblasts from patients deficient for the enzyme hypoxanthine-guanine phosphoribosyltransferase (PRT) activity show very low but nevertheless significant levels of apparent PRT enzyme despite absence of detectable activity (<0.004% of normal) in erythrocytes of the same patients. In fibroblasts this mutant enzyme is more heat labile than the normal enzyme. These findings indicate that PRT deficiency in this disorder is not due to a deletion mutation of the PRT locus.Individual cultured skin fibroblasts from heterozygote females for PRT deficiency show normal, intermediate, or very low levels of PRT activity. The mosaicism demonstrated in the heterozygotes for this X-linked disorder accounts for the cells with normal and very low activities of PRT. Intermediate activity can best be explained by the phenomenon of metabolic cooperation presumably from the transfer of either PRT enzyme or messenger RNA, from normal to mutant cells.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase deficiency: activity in normal, mutant, and heterozygote-cultured human skin fibroblasts. 526 39

SIX INTERSPECIFIC SOMATIC HYBRID CELL LINES WERE DERIVED FROM A MOUSE LINE DEFICIENT IN HYPOXANTHINE: guanine phosphoribosyltransferase (HGPRT) and human diploid cells with normal enzyme activity. Human HGPRT was present in all six hybrids and the clones derived from them. However, in two of the six, and in some clones from another two, human glucose-6-phosphate dehydrogenase (G6PD) was absent. Since the structural loci for both these enzymes are X-linked in man, these findings suggest that these two loci have separated quite frequently through chromosome breakage and that they must be rather far apart on the X chromosome.
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PMID:Mitotic separation of two human X-linked genes in man--mouse somatic cell hybrids. 527 81

Expression of the two X-linked loci glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) and hypoxanthine:guanine phosphoribosyltransferase (HGPRT; EC 2.4.2.8) was studied in single hair follicles of two females who were heterozygous for both of these genes (double heterozygotes). The coupling phase for these two loci was known to be g6pd A and hyprt(-) on the maternal X chromosome and g6pd B and hgprt(+) on the paternal X. Three phenotypic classes of hair follicles were observed in both double heterozygotes: G6pd A follicles with deficient HGPRT activity, G6pd B follicles with normal HGPRT activity, and G6pd AB follicles with intermediate HGPRT activity. These data directly demonstrate one of the predictions of the Lyon hypothesis that for two X-linked loci, those genes in cis position are turned on or off in a cell and its clone, while in trans only one gene or the other is expressed.
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PMID:Expression of two X-linked genes in human hair follicles of double heterozygotes. 528 30

Hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC2.4.2.8), which functions in the metabolic salvage of purines, is encoded by an X-linked gene in man. Partial HPRT deficiencies are associated with gouty arthritis, while absence of activity results in Lesch-Nyhan syndrome (L-N). L-N patients fail to reproduce and the heterozygous state appears to confer no selective advantage. Thus, Haldane's principle predicts that new mutations at the hprt locus must occur frequently in order for L-N syndrome to be maintained in the population. This constant introduction of new mutations would be expected to result in a heterogeneous collection of genetic lesions, some of which may be novel. As we report here, the mutations in the hprt gene of seven L-N patients, selected from an initial survey of 28 patients, have been characterized and all were found to be distinctly different, as predicted. The origin of one unusual mutation has been identified by analysis of DNA from four generations of family members. Further molecular analysis of the origin of new mutations at the hprt locus should aid in resolving the issue of an apparent difference in the frequency of hprt mutations in males and females.
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PMID:Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients. 608 54

A mouse-human somatic cell hybrid clone, deficient in hypoxanthine-guanine phosphoribosyltransferase (HPRT) and containing a structurally normal inactive human X chromosome, was isolated. The hybrid cells were treated with 5-azacytidine and tested for the reactivation and expression of human X-linked genes. The frequency of HPRT-positives clones after 5-azacytidine treatment was 1000-fold greater than that observed in untreated hybrid cells. Fourteen independent HPRT-positive clones were isolated and analyzed for the expression of human X markers. Isoelectric focusing showed that the HPRT expressed in these clones is human. One of the 14 clones expressed human glucose-6-phosphate dehydrogenase and another expressed human phosphoglycerate kinase. Since 5-azacytidine treatment results in hypomethylation of DNA, DNA methylation may be a mechanism of human X chromosome inactivation.
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PMID:Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. 616 95


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