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

Mammalian sex-dosage compensation is mediated by maintaining activity of only one X chromosome. The asynchronous DNA synthesis characterizing the silent human X chromosome is thought to be reversible only during ontogeny of oocytes. We have previously shown that the glucose-6-phosphate dehydrogenase (G6PD) locus (G6PD) on the allocyclic X chromosome in chorionic villi is partially expressed. We now show that in hybrids derived from a clone of chorionic villi cells (heterozygous for G6PD A) and mouse A9 cells, the loci for G6PD, hypoxanthine phosphoribosyltransferase (HPRT) and phosphoglycerate kinase are expressed on both human X chromosomes; the human X chromosomes carrying either G6PD A or B replicate synchronously with each other and with murine chromosomes. The X chromosome with G6PD A was identified as the original late-replicating X, because methylation in the body of the HPRT gene on this chromosome remained characteristic of the inactive X chromosome. These results indicate that X-chromosome inactivation is completely reversible in cells of trophoblast origin; induction of full transcriptional activity is accompanied by acquisition of isocyclic replication, showing an intimate relationship between these processes. The molecular events responsible for this reversal may be similar to those occurring during maturation of oocytes. Chorionic villi and derivative hybrids provide in vitro models for exploring early events that program the single active X chromosome.
 ...
PMID:Complete reactivation of X chromosomes from human chorionic villi with a switch to early DNA replication. 345 82

In marsupials and eutherian mammals, X chromosome dosage compensation is achieved by inactivating one X chromosome in female cells; however, in marsupials, the inactive X chromosomes is always paternal, and some genes on the chromosome are partially expressed. To define the role of DNA methylation in maintenance of X chromosome inactivity, we examined loci for glucose-6-phosphate dehydrogenase and hypoxanthine phosphoribosyltransferase in a North American marsupial, the opossum Didelphis virginiana, by using genomic hybridization probes cloned from this species. We find that these marsupial genes are like their eutherian counterparts, with respect to sex differences in methylation of nuclease-insensitive (nonregulatory) chromatin. However, with respect to methylation of the nuclease-hypersensitive (regulatory) chromatin of the glucose-6-phosphate dehydrogenase locus, the opossum gene differs from those of eutherians, as the 5' cluster of CpG dinucleotides is hypomethylated in the paternal as well as the maternal gene. Despite hypomethylation of the 5' CpG cluster, the paternal allele, identified by an enzyme variant, is at best partially expressed; therefore, factors other than methylation are responsible for repression. In light of these results, it seems that the role of DNA methylation in eutherian X dosage compensation is to "lock in" the process initiated by such factors. Because of similarities between dosage compensation in marsupials and trophectoderm derivatives of eutherians, we propose that differences in timing of developmental events--rather than differences in the basic mechanisms of X inactivation--account for features of dosage compensation that differ among mammals.
 ...
PMID:DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. 347 42

A family is reported in which each of two sisters has a son with no detectable hypoxanthine phosphoribosyltransferase (HPRT) (EC 2. 4. 2. 8) in his erythrocytes, a finding considered pathognomonic of Lesch-Nyhan disease. However, neither has the stigmata of the disease. One boy is neurologically normal, and the other is moderately retarded. There was only a slight increase in urinary uric acid, but the amounts of hypoxanthine and xanthine, and their ratios, were similar to those found in Lesch-Nyhan disease, strongly indicating that excesses of these last two oxypurines are not responsible for the symptomatology in that disease. In contrast to the nondetectable HPRT activity in the red blood cells, leukocyte lysates from the two boys have 10-15% of normal activity, possibly reflecting continuing synthesis of an unstable enzyme. This hypothesis is supported by the demonstration that at 4 degrees C HPRT activity was rapidly lost in the propositus while the activity increased in control subjects. The mother's cells were intermediate between the two. The intact and disrupted leukocytes of the hemizygote, in the absence of added phosphoribosyl converted as much hypoxanthine to inosinate as the normal cell, and appropriate tests indicated that under these circumstances enzyme concentration is not rate limiting whereas the concentration of the cosubstrate, phosphoribosyl pyrophosphate, is. The capacity for normal function in the intact mutant cell is more representative of in vivo conditions than the lysate, which may explain the important modification of clinical symptomatology, the relatively mild hyperuricosuria, and the presence of mosaicism in the circulating blood cells of the heterozygotes. A similar explanation may apply to other genetic diseases in which incomplete but severe enzyme deficiencies are found in clinically normal individuals. An associated deficiency in glucose-6-phosphate dehydrogenase in this family permitted confirmation of previous observations on linkage with hypoxanthine phosphoribosyltransferase.
 ...
PMID:Disparate enzyme activity in erythocytes and leukocytes. A variant of hypoxanthine phosphoribosyl-transferase deficiency with an unstable enzyme. 435 80

Fusion of hypoxanthine phosphoribosyltransferase (HPRT)(-) rat hepatoma cells with HPRT(+) human fibroblasts yielded hybrid clones that grew in HAT selective medium and contained all the rat chromosomes and one to nine human chromosomes. Among the retained chromosomes was the human X chromosome. In all clones backselected in medium containing 8-azaguanine, human X chromosome was absent. Electrophoretic analysis revealed that, without exception, hybrid clones growing in HAT medium had an active HPRT enzyme, either human or rat, or both. When these clones were backselected in 8-azaguanine, they did not show HPRT enzyme activity. Hybrids that contained the human X chromosome also had human glucose-6-phosphate dehydrogenase. The observed reexpression of rat HPRT in hybrid cells derived from HPRT(-) rat cells suggests that a genetic factor from the human cell determined the expression of the rat structural gene for HPRT.
 ...
PMID:Reexpression of the rat hypoxanthine phosphoribosyltransferase gene in rat-human hybrids. 435 57

Somatic cell hybrids have been obtained between SV40-transformed Lesch-Nyhan fibroblasts, which are deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and display glucose-6-phosphate dehydrogenase A (G6PD-A) activity, and late-passage HGPRT-positive W138 human embryo fibroblasts, which display G6PD-B activity. The human-human hybrid clones, which display G6PD-A and G6PD-B and heteropolymers of the two enzyme forms, have the same growth characteristic as the SV40-transformed parental cells and behave as continuous cell lines. The SV40 tumor antigen, the gene for which has been assigned to human chromosome 7, is present in all clones examined.
 ...
PMID:Positive control of transformed phenotype in hybrids between SV40-transformed and normal human cells. 436 42

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.
 ...
PMID:Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. 616 95

A mouse-human cell hybrid clone retaining an inactive human X chromosome was treated with 5-azacytidine. Following treatment, expression of the X-linked enzyme markers, hypoxanthine-guanine phosphoribosyltransferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), phosphoglycerate kinase (PGK), and alpha-galactosidase A (GLA) was examined. Results presented here show that 45 of the 62 clones positive for human HPRT expressed human GLA, while only four of 68 clones negative for human HPRT expressed human GLA. These results strongly suggest that there is coordinate reactivation of GLA and HPRT. Reactivated expression of G6PD was studied in detail. The studies show that 5-azacytidine can induce heritable changes in the inactive human X chromosome resulting in the expression of G6PD activity at a level lower than that from an active human X chromosome.
 ...
PMID:Frequency of reactivation and variability in expression of X-linked enzyme loci. 620 21

Bovine embryonic trachea cells were hybridized with mouse A9 cells deficient in hypoxanthine phosphoribosyltransferase, and cattle-mouse hybrid cells clones were isolated after HAT/ouabain selection. In these interspecific cell hybrids, bovine glucose-6-phosphate dehydrogenase, alpha-galactosidase, and phosphoglycerate kinase were expressed concordantly with bovine HPRT. Their expression depended on the presence of bovine X chromosome. These data indicated that the genes for G6PD, PGK, and HPRT are linked and can be assigned to the bovine X chromosome.
 ...
PMID:The bovine genes for phosphoglycerate kinase, glucose-6-phosphate dehydrogenase, alpha-galactosidase, and hypoxanthine phosphoribosyltransferase are linked to the X chromosome in cattle-mouse cell hybrids. 625 51

Pig--mouse somatic cell hybrids were obtained from fusion of HPRT--mouse cells (RAG) and pig lymphocytes. The pig-mouse hybrids examined apparently retained on the average only 9 to 15 pig chromosomes. Seven of the hybrid clones were karyotyped to determine the pig chromosome constitution, and the same hybrid clones were tested electrophoretically for the expression of pig hypoxanthine-guanine phosphoribosyltransferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), and alpha-galactosidase (alpha-GAL) phenotypes. All five of the hybrid clones which had retained the pig X-chromosome exhibited concordant expression of pig HPRT, G6PD, and alpha-GAL enzymes. These data indicate that the genes HPRT, G6PD, and alpha-GAL are located on the X-chromosome of the domestic pig.
 ...
PMID:The localization of genes for HPRT, G6PD, and alpha-GAL onto the X-chromosome of domestic pig (Sus scrofa domesticus). 630 43

We have used a cloned cDNA for hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to analyze the HGPRT gene and mRNA in an HGPRT-deficient mutant of Chinese hamster cells (RJK10) and its HGPRT-positive revertants. By Southern blot analysis, no DNA rearrangements were detected within the genes from any of the cell lines examined. However, four of five spontaneous revertants each contained 10- to 20-fold more copies of the HGPRT gene than did RJK10 or wild-type cells. In contrast, the gene was not amplified in four mutagen-induced revertants. The RJK10 mutation did not alter the size or concentration of HGPRT mRNA and representatives of the revertants contained the mRNA in amounts proportional to the number of genes they carried. Examples of clones with either stable or unstable gene amplification were identified and their HGPRT-positive phenotypes were shown to be dependent on the gene amplification. In a stably amplified revertant, the extra genes were found to be syntenic with the X chromosome marker glucose-6-phosphate dehydrogenase. In an unstable revertant only one of the 10 to 20 copies of the gene could be shown to be X linked. Thus, we found that RJK10 can revert by at least two distinct mechanisms: amplification of the HGPRT gene, which occurred spontaneously, or point mutation, which predominated after exposure to mutagens.
 ...
PMID:Amplification versus mutation as a mechanism for reversion of an HGPRT mutation. 658 54


<< Previous 1 2 3 4 Next >>