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)

The patient, H.Chr.B., was among the first reported with hyperuricemia and central nervous system symptoms. He has been found to have a variant of hypoxanthine guanine phosphoribosyl transferase (HPRT; E.C.2.4.2.8) distinct from the enzyme present in patients with the Lesch-Nyhan syndrome. The patient had chroeoathetosis, spasticity, dysarthric speech, and hyperuricemia. However, his intelligence was normal and he had no evidence of self-mutilation. There was no activity of HPRT in the lysates of erythrocytes and cultured fibroblasts when analyzed in the usual manner. Using a newly developed method for the study of purine metabolism in intact cultured cells, this patient was found to metabolize some 9% of 8-14C-hypoxanthine, and 90% of the isotope utilized was converted to adenine and guanine nucleotides. In contrast, cells from patients with the Lesch-Nyhan syndrome were virtually completely unable to convert hypoxanthine to nucleotides. The patient's fibroblasts were even more efficient in the metabolism of 8-14C-guanine, which was utilized to the extent of 27%, over 80% of which was converted to guanine and adenine nucleotides. The growth of the cultured fibroblasts of this patient was intermediate in media containing hypoxanthine aminopterin thymidine (HAT), whereas the growth of Lesch-Nyhan cells was inhibited and normal cells grew normally. Similarly in 8-azaguanine, 6-thioguanine, and 8-azahypoxanthine, the growth of the patient's cells was intermediate between normal and Lesch-Nyhan cells. These observations provide further evidence for genetic heterogeneity among patients with disorders in purine metabolism involving the HPRT gene. They document that this famous patient did not have the Lesch-Nyhan syndrome.
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PMID:Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome. 52 96

The site of association of the human transgenome and host murine chromosomes was determined in several subclones of a stable human/mouse transformed cell line. Chromosomes were transferred from each of three transformed subclones into Chinese hamster recipient cells, and selection was applied for the expression of human transgenome-encoded HPRT. A series of trispecific microcell hybrids was isolated and characterized for each subclone. Evidence is presented that, within a given transformed subclone, only a single host (murine) chromosome was associated with the human transgenome. This contrasts with previous results which utilized a newly stabilized transformed cell line as the microcell donor and in which a variety of chromosomal sites of association existed. The results presented here support the view that the heterogeneity of transgenome association (integration) sites in newly stabilized transformants was due to the fact that these populations were multiclonal mixtures resulting from independent stabilization events. The initial heterogeneity in the population was subsequently reduced upon prolonged cultivation, as a subset of the original population became predominant.
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PMID:Somatic cell genetic analysis of transgenome integration. 54 18

The behaviour of human cells arrested in mitosis can be severely perturbed so as to generate numerous small minisegregants containing very few chromosomes. These cells can be separated according to size and DNA content and fused with intact cells. In this paper we describe the production and some properties of proliferating cell hybrids generated by fusion of human minisegregant cells derived from a HeLa strain with mouse A9 cells deficient in hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8). The hybrids were shown to contain up to 10 human chromosomes including a single X. Independently derived hybrid clones were quantitatively characterized and compared with the parental phenotypes with respect to HPRT. Human isozymes of each of the 3 enzymes HPRT, glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and phosphoglycerate kinase (EC 2,7.2.3) were found. Tests to evaluate both structure and function of HPRT were utilized. The specific activity of HPRT of more than 10 hybrids tested was approximately 10% that of the HeLa parent. Structural characterization of HPRT from hybrid cells as evidenced by heat inactivation and electrophoretic mobility results in a 'human-like' phenotype. Functional characterization of parental HPRT results in kinetic constants for cofactor and substrate which do not permit distinction of human and of human and mouse enzymes; HPRT from the minisegregant hybrids had normal kinetic constants. The reduced specific activity of HPRT in the hybrids is discussed in terms of the inability of the mouse environment to regulate the full expression of the human structural gene.
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PMID:Transfer of human chromosomes via human minisegregant cells into mouse cells and the quantitation of the expression of hypoxanthine phosphoribosyltransferase in the hybrids. 56 87

Four diploid somatic recombinants were isolated from hybrids either between or within two diploid cell lines of a male Indian muntjac after HVJ virus-mediated cell fusion. Both parental lines had a normal male karyotype, 7,X,Y1,Y2, in which the largest autosomal pair was heteromorphic with respect to the size of the secondary constriction (1h+/1h-), C bands, and nucleolar organizers. Of the four recombinants, three showed a 6,XX,1h+/1h+ or 1h+/1h- karyotype, the remaining one a 7,XY1Y2,1h+/1h+. No late-replicating X chromosome was found in the XX recombinants, although it was demonstrated in the natural XX line, suggesting the presence of two active X chromosomes in the former. The G6PD, PGK, and HPRT activities were proportional to the number of active X chromosomes present in all cell types examined, indicating their X-linkage, whereas the same level of activities obtained for LDH and 6PGD indicated their autosomal linkage.
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PMID:Euploid somatic recombinants with two active X or XY (1)Y(I) chromosomes isolated from cultured male Indian Muntjac cells after HVJ virus fusion, and their use for gene assignment. 56 83

Embryos from XO female mice begin development with half the activity levels of an enzyme (HPRT) coded for by a gene on the X chromosome, compared with embryos from XX females. Groups of unfertilized eggs and individual embryos at the 8-cell, morula and blastocyst stages were assayed for HPRT activity. An autosomally coded enzyme (APRT) was assayed simultaneously in the same reaction mix as a control. There is a substantial increase in HPRT activity by the 8-cell stage. However, the mean activity of HPRT in embryos of XO mothers remains half that in embryos of XX mothers. This suggests a significant maternally inherited component of HPRT activity in 8-cell embryos. By the 9- to 16-cell morula stage the HPRT activities in the two groups of embryos become similar due, presumably, to a transition to embryo-coded activity; HPRT activities in individual morulae from XX mothers show a bimodal distribution consistent with the hypothesis that both X-chromosomes are active in XX embryos at this stage.
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PMID:X-chromosome activity in preimplantation mouse embryos from XX and XO mothers. 56 62

In several patients with different degrees of HPRT deficiencies, residual activities have been determined in both lysed and intact erythrocytes. No close correlation could be found between the degree of HPRT deficiency and the severity of the clinical expression. Unless HPRT activity in both intact and lysed erythrocytes was below detection level, the residual activity in intact red blood cells was higher than in lysates. Tissue-specific heterogeneity was illustrated with a patient suffering from X-linked gout. Lysates from erythrocytes, leukocytes, and cultured fibroblasts showed 1%, 8%, and 100% of normal HPRT activity, respectively. Characterization of the erythrocyte and fibroblast HPRT from this patient showed no kinetic abnormalities. However, there was a decreased heat stability. It is concluded that for a better understanding of the pathophysiology in HPRT deficiency studies on nucleated cells from the different tissues are needed.
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PMID:Molecular and tissue-specific heterogeneity in HPRT deficiency. 57 18

The toxic and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on cultured diploid human fibroblasts were studied. When 10(5) cells per 60 mm dish were exposed to MNNG for 4 h in Ham's medium F10 containing 0.02 M HEPES buffer at pH 6.8, MNNG concentrations of less than 1 X 10(-6) M resulted in cell survivals near 100%, while the average survival was less than one percent at concentrations greater than 5 X 10(-6) M. After treatment with MNNG, cells were subjected to selection using optimal conditions for the detection of diploid human fibroblasts that are resistant to the guanine-analogs AG and TG because they contain altered or deficient HPRT. The induced mutant frequency was maximized by allowing a 5 to 7 day post-treatment interval for the expression of the mutant phenotype and by replating the cells at the beginning of selection at a population density of less than 450 cells per cm2. Careful attention was given to counting statistically adequate numbers of mutants and to accurately determining cell survival and replating cloning efficiencies. Independent dose-response experiments gave induced mutant frequencies as high as 7.0 X 10(-4) to 8.8 X 10(-4) mutants per viable cell at about 5% survival, compared to a spontaneous mutation rate of 3.7 X 10(-6) to 7.2 X 10(-6) mutants per cell generation. The AGr mutants observed after treatment with MNNG were phenotypically stable and closely resembled prototype AGr cultures derived from humans who have inherited mutant X-chromosomal alleles for HPRT.
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PMID:Quantification of chemical mutagenesis in diploid human fibroblasts: induction of azaguanine-resistant mutants by N-methyl-N'-nitro-N-nitrosoguanidine. 62 4

A variant form of hypoxanthine-guanine phosphoribosyl transferase has been found in a neurologically normal pediatric patient who presented with hematuria an episodes of oliguria and azotemia. The level of erythrocyte enzyme activity was 3% of normal. Electrophoretic mobility was more rapid than normal. The Km for hypoxanthine was approximately ten times normal. Immunochemical analysis indicated that the variant enzyme cross reacted with antibody to normal HPRT. A system is described for the systematic characterization of a variant HPRT.
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PMID:A distinct human variant of hypoxanthine-guanine phosphoribosyl transferase. 63 76

Analysis of six enzymes using starch gel electrophoresis indicates that autosomal and X-linked genes of both parental species are expressed normally in M. musculus X M. caroli hybrids. There is no evidence for allelic repression for the four autosomally inherited enzymes. Banding patterns for G6PD and PGK-1 indicate that X-chromosome inactivation occurs and that the maternally derived M. musculus X-chromosome is preferentially expressed in the yolk sac. Despite normal genetic expression none of the four adult female hybrids was fertile and the male hybrids tended to be retarded during fetal development. The routine production of fetal M. musculus X M. caroli hybrids, heterozygous for three X-linked genes coding for G6PD, PGK-1, and HPRT, should provide an excellent system for the analysis of X-chromosome expression and an alternative to the mule for studies of hybrid reproduction and development.
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PMID:Mus musculus x Mus caroli hybrids: mouse mules. 74 73

A medium is described which can be used for the selection of somatic cell hybrids between HPRT- and APRT- mutant cells. This medium, called GAMA, contains as its relevant constituents the following: the purines guanine and adenine and the purine biosynthetic pathway inhibitors mycophenolic adic, which blocks conversion of adenine ribonucleotides to guanine ribonucleotides, and azaserine, which blocks de novo purine synthesis.
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PMID:A selective medium (GAMA) for the isolation of somatic cell hybrids from HPRT- and APRT- mutant cells. 76 86


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