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)

The possible factors in the pathogenesis of the brain damage and megaloblastic anaemia in the Lesch-Nyhan syndrome are discussed. Disordered growth and function appear to be limited to the brain, bone marrow and general body stature, yet the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8, HGPRT), although present in variable amounts in different tissues, is ubiquitous, a fact which suggests that other factors than HGPRT deficiency alone determine the pattern of tissue damage. Recent evidence suggests that the specific tissue damage in the Lesch-Nyhan syndrome is due to lack of NGPRT in tissues with relatively reduced purine de novo capability and a greater dependence on purine salvage pathways at certain stages in their development for their supply of purine ribonucleotides. This evidence is presented together with possible mitigating factors operating in the bone marrow.
 ...
PMID:Factors in the pathogenesis of the brain damage and anaemia in the Lesch-Nyhan syndrome. 24 94

Heterozygotes for the Lesch-Nyhan syndrome have normal hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity in their erythrocyte lysates. However, HGPRT activity in lysates from heterozygotes for the partial HGPRT deficiency states is often between that seen in the affected hemizygote and the normal. An autoradiographic technique was developed which demonstrated the HGPRT activity in individual erythrocytes in vitro. This technique revealed that heterozygotes for the Lesch-Nyhan syndrome had erythrocytes that contained normal HGPRT activity but heterozygotes for the partial deficiency had two populations of erythrocytes, one with normal HGPRT activity and the other with the reduced HGPRT activity characteristic of the hemizygote. With these latter heterozygotes, the proportion of HGPRT-deficient erythrocytes agreed with that calculated on the basis of enzyme activity in erythrocyte lysates.
 ...
PMID:Hypoxanthine-guanine phosphoribosyltransferase activity in individual erythrocytes: autoradiographic studies in heterozygotes. 24 95

Hypoxanthine phosphoribosyltransferase (HPRT, IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) can be purified 5-to 10,000-fold from extracts of HeLa (human) cells by a three-step procedure consisting of high-speed centrifugation, adsorption to Sepharose-conjugated HPRT antibody, and sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Purified enzyme labeled in vivo with radioactive lysine, arginine, or methionine was digested with trypsin and the tryptic peptides were separated by column chromatography on Bio-Rad cation exchanger Aminex A-5. Less than 50 ng (2 pmol) of HPRT is required to produce a tryptic peptide pattern. A methionine-labeled peptide was identified as the COOH-terminus because it was not labeled with either lysine or arginine. We have compared the tryptic peptide patterns of normal HeLaHPRT and a crossreacting HPRT protein lacking enzyme activity from HeLa mutant H23 [Milman et al. (1976) Proc. Natl. Acad. Sci. USA 73, 4589--4593]. The mutant protein has a new lysine-labeled peptide, but the chromatography patterns of arginine- or methionine-labeled peptides appear identical to those of the normal protein. The appearance in the H23 mutant HPRT protein of a new tryptic peptide provides strong evidence for a mutation in the HPRT structural gene. The tryptic peptide patterns were used to determine the total number of residues of labeled amino acid in the protein, and the values are reasonably consistent with those determined by conventional amino acid analysis pf erythrocyte HPRT.
 ...
PMID:Tryptic peptide analysis of normal and mutant forms of hypoxanthine phosphoribosyltransferase from HeLa cells. 26 86

The human hypoxanthine phosphoribosyl-transferase (IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) gene (hprt) has been serially transferred to mouse cells and then to Chinese hamster fibroblasts by two cycles of metaphase chromosome isolation and incubation with recipient cells. Human metaphase chromosomes were incubated with mouse A9 cells deficient in hypoxanthine phosphoribosyltransferase, and independent colonies expressing the human species form of this gene were isolated in a selective medium. Metaphase chromosomes isolated from two of these clonal lines were incubated with Chinese hamster fibroblasts deficient in hypoxanthine phosphoribosyltransferase; five resulting independent colonies again expressed the human species of this gene. The transfer frequencies in the two cycles of chromosome-mediated gene transfer were similar (about 10(-7)). These results indicate that the transferred human chromosome fragment is closely associated with the chromosomes of the mouse A9 cells and it is probably integrated into the chromosomal DNA of the recipient cell.
 ...
PMID:Serial transfer of a human gene to rodent cells by sequential chromosome-mediated gene transfer. 26 45

Trispecific microcell hybrids were prepared by transferring limited numbers of chromosomes from a human/mouse gene-transfer cell line to a Chinese hamster recipient line. The donor cells employed were murine L-cells that stably expressed the human form of the enzyme hypoxanthine phosphoribosyltransferase. Karyotypic, zymographic, and back-selection tests of the resulting human/mouse/Chinese hamster microcell hybrids provided strong genetic evidence for a stable association of the human transgenome with host murine chromosomes in stable gene-transfer cell lines. This association, which may represent physical integration of the transgenome into the host cell genome, occurred at multiple chromosomal sites.
 ...
PMID:Stable association of the human transgenome and host murine chromosomes demonstrated with trispecific microcell hybrids. 26 44

The specific activity of hypoxanthine-guanine phosphoribosyltransferase (IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) is increased up to 58-fold in unstable gene transferents produced by the transfer of cell-free chromosomal material from one mouse L cell line to another; the specific activity of this enzyme returns to normal levels when the transferred gene becomes stabilized. This phenomenon, which is not observed in comparable heterospecific transfers, may be an effect of gene dosage (multiple copies of the transferred genetic fragment in the unstable gene transferents), or it may represent an escape of the unstably inherited gene from the normal regulatory mechanisms of the recipient cell.
 ...
PMID:Overexpression of an unstably inherited gene in cultured mouse cells. 26 46

With an assay that quantitates the transfer of 6-thioguanylic acid from hypoxanthine phosphoribosyltransferase (IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8)-positive donor cells to negative recipient cells through gap junctions, differences in contact-mediated communication between normal and transformed human cells in culture have been detected. We have compared cells cultured from human tumors and simian virus 40-transformed cells with the normal human fibroblasts from which they were derived as well as with gap junction-deficient L cells. The communication, which is extensive in normal cells, is significantly reduced when transformed cells are used as either donors or recipients in the contact-feeding assay. Furthermore, the reduction in the transfer of nucleotides is enhanced when transformed cells are used as both donors and recipients, indicating a dosage effect or synergism, independent of enzyme activity. Fetal cells have a contact-feeding phenotype intermediate between that of normal and that of transformed cells. We suggest that the decrease in communication of nucleotides in transformed cells reflects quantitative or qualitative changes in membrane components responsible for gap junction formation.
 ...
PMID:Comparison of contact-mediated communication in normal and transformed human cells in culture. 27 Jun 94

Mutagenized stem cells of a cultured mouse teratocarcinoma cell line were selected for resistance to the purine base analog 6-thioguanine. Cells of a resistant clone were completely deficient in activity of the enzyme hypoxanthine phosphoribosyltransferase (HPRT, IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8), the same X-linked lesion as occurs in human Lesch-Nyhan disease. After microinjection into blastocysts of another genetic strain, the previously malignant cells successfully participated in normal embryogenesis and tumor-free, viable mosaic mice were obtained. Cells of tumor lineage were identified by strain markers in virtually all tissues of some individuals. Mature function of those cells was evident from their tissue-specific products (e.g., melanins, liver proteins). These mutagenized teratocarcinoma cells are therefore developmentally totipotent. Retention of the severe HPRT deficiency in the differentiated state was documented in extracts of mosaic tissues by depressed specific activity of the enzyme, and also by presence of unlabeled clones in autoradiographs of explanted cells incubated in [(3)H]hypoxanthine. Some mosaic individuals had mutant-strain cells in only one or a few tissues. Such animals may provide unique opportunities to identify the tissue sources of particular aspects of the complex disease syndrome. The tissue distribution of HPRT-deficient cells suggests that selection against them is particularly strong in blood of the mosaic mice, as is already known to be the case in human heterozygotes. This phenotypic parallelism supports the expectation that afflicted F(1) male mice that might be obtained from mutant germ cells can serve as a model of the human disease.
 ...
PMID:Mosaic mice with teratocarcinoma-derived mutant cells deficient in hypoxanthine phosphoribosyltransferase. 27 82

Two brothers were found to have athetoid cerebral palsy, mental and growth retardation and evidence of self mutilation. One had passed a renal calculus and both had high serum uric acid levels. The diagnosis of Lesch-Nyhan syndrome was confirmed by the finding of low levels of hypoxanthine-guanine phosphoribosyl transferase in erythrocytes and by autoradiography of fibriblasts. The mother, maternal grandmother, a female sibling and a maternal aunt were identified as carriers of the X-linked mutation which was responsible for the enzyme deficiency in the two male siblings.
 ...
PMID:The Lesch-Nyhan syndrome: a family study. 27 69

Transformation frequencies of 4 x 10(-5) were obtained in chromosome-mediated gene transfer experiments using human cell line HeLa S3 as donor and mouse cell line A9 as recipient. This high frequency of interspecific transformation was achieved by treating the recipient cells with dimethylsulfoxide in addition to other facilitators. The high frequency of transformation correlated positively with transgenome size on the basis of both co-transfer of linked markers and chromosome analysis. The syntenic human markers glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADP(+) 1-oxidoreductase, EC 1.1.1.49) and phosphoglycerate kinase (ATP:3-phospho-D-glycerate 1-phosphotransferase, EC 2.7.2.3) were sometimes transferred together with the selected X-linked prototrophic marker hypoxanthine phosphoribosyltransferase (IMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) into murine somatic cells. Donor human chromosome material could be demonstrated cytologically in some of the transformed cell lines. Transformants exhibited various rates of loss of the human hypoxanthine phosphoribosyltransferase marker when grown under nonselective conditions. These results reveal a broader range of possible interspecific transgenome sizes than has been recognized in the past. The largest transgenomes consist of cytologically detectable donor fragments and contain syntenic markers that are not closely linked to the selected marker.
 ...
PMID:Co-transfer of human X-linked markers into murine somatic cells via isolated metaphase chromosomes. 27 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>