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)

A hybrid cell line (R21/B1) containing a truncated human chromosome 6 (6pter-6q21) and a human Y chromosome on a hamster background was irradiated and fused to A23 (TK-) or W3GH (HPRT-) hamster cells. Clones containing expressed HLA class I genes (4/40) were selected using monoclonal antibodies. These clones were recloned and analyzed with a panel of probes from the HLA region. One hybrid (4G6) contained the entire HLA complex. Two other hybrids (4J4 and 4H2) contained only the HLA class I region, while the fourth hybrid (5P9) contained HLA class I and III genes in addition to other genes located in the 6p21 chromosomal region. In situ hybridization showed that the hybrid cells contained more than one fragment of human DNA. Alu and LINE PCR products were derived from these cells and compared to each other as well as to products from two somatic cell hybrids having the 6p21 region in common. The PCR fragments were then screened on conventional Southern blots of the somatic cell hybrids to select a panel of novel probes encompassing the 6p21 region. In addition, the origin of the human DNA fragments in hybrid 4J4 was determined by regional mapping of PCR products.
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PMID:Isolation of probes specific to human chromosomal region 6p21 from immunoselected irradiation-fusion gene transfer hybrids. 190 83

The effects of low-fluence exposures to (Pu, Be) neutrons (En = 4.2 MeV) have been studied in a sensitive human B-lymphoblastoid cell line, TK6. Mutations were scored for two genetic loci, hypoxanthine phosphoribosyltransferase (hgprt) and thymidine kinase (tk), as a function of dose and dose rate. For exposures limited to less than one cell cycle, the mutation frequency for the hgprt locus was 1.92 X 10(-7)/cGy. When exposures were protracted over multiple cell generations, mutation yields were increased to 6.07 X 10(-7)/cGy. Similar yields were obtained for the induction of tk-deficient mutants with a normal cell generation time (tk-ng) when exposures were carried out at very low dose rates over multiple cell generations. In the series of data presented here, the results obtained for short-duration neutron exposures are compared with data obtained for monoenergetic heavy charged particles of defined linear energy transfer (LET) produced at the BEVALAC accelerator at Lawrence Berkeley Laboratory. TK6 cells have been exposed to beams ranging in atomic number from 20Ne to 40Ar over an energy range from 330 to 670 MeV/amu. Mutation induction was evaluated for both loci for a subset of these beams. The results obtained with 20Ne ions of 425 MeV/amu (LET = 32 keV/microns) and 28Si ions of 670 MeV/amu (LET = 50 keV/microns) closely resemble the mutation yields obtained for brief exposures to (Pu, Be) neutrons. The nature of alterations in DNA structure induced within the tk locus of tk-ng mutants is reviewed for a series of neutron-induced mutants and a series of mutants induced by exposure to 40Ar ions (470 MeV/amu, LET = 95 keV/microns). The mutational spectra for these two types of mutants were similar and were dominated by allele loss mutations. Multilocus deletions inclusive of the c-erbA1 locus were common among tk-deficient mutants induced by these densely ionizing radiations. For the mutants induced by 40Ar ions, it is likely that the mutations were produced by the traversal of the chromosome by a single particle.
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PMID:Perspectives on fast-neutron mutagenesis of human lymphoblastoid cells. 192 55

Studies from several laboratories worldwide have developed a large database for in vivo hypoxanthine-guanine phosphoribosyltransferase gene mutations in human T-lymphocytes. Sufficient differences have been found thus far between the spectrum for spontaneous mutations in adults and that observed in the fetus to suggest fundamental differences in in vivo mutagenic mechanisms at these two life stages. In adults, only approximately 15% of hypoxanthine-guanine phosphoribosyltransferase mutations have structural alterations on Southern blots, while in the fetus 75% of mutations show alterations of which one-half are deletions of exons 2 and 3. We have now sequenced the breakpoint sites for these specific deletions in 18 mutant lymphocyte clones isolated from 13 normal newborns. Three classes of deletions were found. Each class had the same intron 1 breakpoint but a different intron 3 breakpoint. These mutations have all the signatures of a V(D)J recombinase-mediated event (a 5' consensus heptamer, 3' consensus heptamer and nonamer, nibbling, non-germline-encoded nucleotides, P-nucleotides). At the 3' breakpoint of the most common class (comprising 83% of the mutants) a perfect heptamer can be created by postulating a hairpin loop which could attain a Z-DNA configuration. This feature may indicate recombinase preference for certain DNA structures. These results implicate the V(D)J recombinase in illegitimate events causing mutation in this housekeeping gene during T-cell development. Inactivation of genes involved in the control of growth and differentiation (e.g., tumor suppressor genes) by this mechanism may have important implications for cancer development.
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PMID:V(D)J recombinase-like activity mediates hprt gene deletion in human fetal T-lymphocytes. 193 63

The Lesch-Nyhan syndrome is a severe X chromosome-linked human disease caused by a virtual absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. A partial deficiency in the activity of this enzyme can result in gouty arthritis. To determine the genetic basis for reduction or loss of enzyme activity, we have amplified and sequenced the coding region of HPRT cDNA from four patients: one with Lesch-Nyhan syndrome (HPRTPerth) and three with partial deficiencies of HPRT activity, which have been designated HPRTUrangan, HPRTSwan and HPRTToowong. In all four patients, the only mutation identified was a single base substitution in exons 2 or 3 of the coding region, which in each case predicts a single amino acid substitution in the translated protein. Each base change was confirmed by allele-specific amplification of the patient's genomic DNA. It is interesting to note that the mutation found for HPRTPerth is identical to that reported for HPRTFlint. It appears that the two mutations are de novo events.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification. 193 71

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) reacts with 12 nucleophilic sites in DNA to induce a variety of lesions, but O6-methylguanine (O6-MeG) and O4-methylthymine are the most effective premutagenic lesions produced, mispairing with thymine and guanine, respectively. O6-MeG is repaired by O6-alkylguanine-DNA alkyltransferase (AGT), which removes the methyl group from the O6 position and transfers it to itself, rendering the transferase inactive. When diploid human fibroblasts were exposed to 25 microM, O6-benzylguanine (O6-BzG) in the medium for 3 h, their level of AGT activity was dramatically reduced, to a level of at most 1.6% of the control. Populations of cells pretreated with this level of O6-BzG for 2 h or not pretreated, were exposed to MNNG at a concentration of 2, 4 or 6 microM in the presence or absence of O6-BzG and assayed for survival of colony-forming ability and the frequency of 6-thioguanine-resistant cells (mutations induced in the HPRT gene). O6-BzG (25 microM) was also present in the appropriate half of the cells during the 24 h immediately following exposure to MNNG. This 27-h exposure to O6-BzG alone had no cytotoxic or mutagenic effect on the cells but significantly increased the cytotoxicity and mutagenicity of MNNG, increasing the mutant frequency to that found previously in human cells constitutively devoid of AGT activity. At doses of 2 microM and 4 microM MNNG, the mutant frequency observed with the AGT-depleted cells was 120 x 10(-6) and 240 x 10(-6), respectively; in the cells with abundant AGT activity, these values were 10 x 10(-6) and 20 x 10(-6), respectively. DNA-sequence analysis of the coding region of the HPRT gene in 36 independent mutants obtained from MNNG-treated AGT-depleted populations and 36 from the control populations showed that even though AGT repair lowered the frequency of mutants by more than 90%, it did not affect the kinds of mutations induced by MNNG nor the strand distribution of the premutagenic guanine lesions. In mutants from the AGT-depleted cells, there were 26 base substitutions and 13 putative splice site mutations; in the control, there were 25 base substitutions and 11 splice site mutations. All but two substitutions involved G.C with 92% being G.C----A.T. In both sets, approximately 73% of the premutagenic lesions were located in the nontranscribed strand.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of O6-alkylguanine-DNA alkyltransferase on the frequency and spectrum of mutations induced by N-methyl-N'-nitro-N-nitrosoguanidine in the HPRT gene of diploid human fibroblasts. 194 54

Cloned cDNAs representing the entire, homologous (80%) translated sequences of human phosphoribosylpyrophosphate synthetase (PRS) 1 and PRS 2 cDNAs were utilized as probes to localize the corresponding human PRPS1 and PRPS2 genes, previously reported to be X chromosome linked. PRPS1 and PRPS2 loci mapped to the intervals Xq22-q24 and Xp22.2-p22.3, respectively, using a combination of in situ chromosomal hybridization and human x rodent somatic cell panel genomic DNA hybridization analyses. A PRPS1-related gene or pseudogene (PRPS1L2) was also identified using in situ chromosomal hybridization at 9q33-q34. Human HPRT and PRPS1 loci are not closely linked. Despite marked cDNA and deduced amino acid sequence homology, human PRS 1 and PRS 2 isoforms are encoded by genes widely separated on the X chromosome.
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PMID:Cloning of cDNAs for human phosphoribosylpyrophosphate synthetases 1 and 2 and X chromosome localization of PRPS1 and PRPS2 genes. 196 53

We used the X-linked restriction fragment length polymorphism (RFLP)-methylation strategy to study the clonal basis of the myelodysplastic syndrome (MDS) in seven patients. RFLP-methylation analysis was performed on cell populations from bone marrow (BM) aspirates and peripheral blood using probes specific for the hypoxanthine phosphoribosyltransferase (HPRT) or phosphoglycerate kinase (PGK) gene regions. Density gradient centrifugation methods were used to separate granulocytes and monocytes, and T lymphocytes were positively selected by CD2 (a pan-T marker) immunoconjugated magnetic beads. Cell populations from BM aspirates in 6 of the 7 patients with MDS showed a monoclonal pattern of X-inactivation. The neutrophilic and T-lymphocytic cell fractions were analyzed in 4 of the 6 patients, and the monocytic cell fraction in one of these, and all fractions analyzed showed a similar monoclonal pattern. In 2 of the latter 4 patients, both of whom had normal karyotypes, DNA from a skin biopsy showed a polyclonal pattern. Our data suggest that MDS is a clonal disorder, even in the absence of detectable cytogenetic abnormalities, and that the abnormal clone is capable of myeloid, monocytic, and lymphoid differentiation.
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PMID:Clonal studies in the myelodysplastic syndrome using X-linked restriction fragment length polymorphisms. 197 Apr 87

Accumulated data using functional, morphologic, and histochemical analysis suggests that follicular proliferations in the thyroid include polyclonal and monoclonal patterns with encapsulated follicular adenomas most frequently monoclonal, and other nodules generally polyclonal. However, examples of polyclonal carcinomas or adenomas raise the possibility that histologically similar lesions may arise through different pathogenetic mechanisms. The authors have performed a clonal analysis of histologically benign and malignant thyroid nodules in seven women using HPRT (hypoxanthine phosphoribosyl transferase) and PGK (phosphoglycerate kinase) restriction fragment length polymorphisms (RFLPs) on the X chromosome. These RFLPs used in concert with methylation-sensitive restriction endonucleases HpaII and HhaI permit distinction of active and inactive X chromosomes. DNA from a multinodular goiter showed equal sensitivity of both X chromosome RFLP alleles to a methylation-sensitive restriction endonuclease, consistent with a polyclonal origin. In contrast, three solitary follicular nodules and three carcinomas displayed predominant sensitivity of a single RFLP allele, consistent with a monoclonal origin. Although further detailed studies will be necessary to understand polyclonal origins reported for some adenomas, our data from a limited number of samples supports a predominantly monoclonal origin, and possible neoplastic pathogenesis, for many solitary adenomatous nodules in the thyroid.
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PMID:Clonal analysis of solitary follicular nodules in the thyroid. 197 86

As the pathogenesis of pituitary adenomas remains unclear, the tumor clonal composition of these common neoplasms was studied. Clonality was determined in female patients by analysis of restriction fragment length polymorphisms of the X-chromosome genes hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase in conjunction with their respective methylation patterns. Peripheral lymphocyte DNA was screened from 62 female patients undergoing transsphenoidal surgery for pituitary adenoma. Eleven patients were heterozygous for the BglI site on PGK, 4 for the BamHI site on HPRT, and 1 patient for both sites. Of these 16 patients, 3 had acromegaly, 4 had Cushing's disease, 7 had hyperprolactinemia, and 2 were clinically nonfunctional. After surgery, morphological study, including immunohistochemistry and electron microscopy of the pathological specimens, allowed a direct comparison between clonality and tumor cell type. Control fresh normal pituitary tissue was found to be polyclonal. The following tumors were monoclonal: all 3 somatotroph adenomas, 4 of 4 lactotroph tumors, 3 of 4 corticotroph cell adenomas, a gonadotroph adenoma, and a nonsecretory adenoma. A mixed plurihormonal adenoma was polyclonal, as were 2 tumors consisting of adenomatous lactotrophs interspersed with nontumorous adenohypophyseal pituitary tissue and one corticotroph adenoma mixed with normal pituitary tissue. Functional pituitary adenomas derived from somatotrophs, corticotrophs, or lactotrophs and nonsecretory tumors are monoclonal in nature, suggesting that somatic cell mutations precede clonal expansion of these cells and play a major role in pituitary tumorigenesis.
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PMID:Clonal origin of pituitary adenomas. 197 59

The purpose of this study was to use DNA transfection and microcell chromosome transfer techniques to engineer a human chromosome containing multiple biochemical markers for which selectable growth conditions exist. The starting chromosome was a t(X;3)(3pter----3p12::Xq26----Xpter) chromosome from a reciprocal translocation in the normal human fibroblast cell line GM0439. This chromosome was transferred to a HPRT (hypoxanthine phosphoribosyltransferase)-deficient mouse A9 cell line by microcell fusion and selected under growth conditions (HAT medium) for the HPRT gene on the human t(X;3) chromosome. A resultant HAT-resistant cell line (A9(GM0439)-1) contained a single human t(X;3) chromosome. In order to introduce a second selectable genetic marker to the t(X;3) chromosome, A9(GM0439)-1 cells were transfected with pcDneo plasmid DNA. Colonies resistant to both G418 and HAT medium (G418r/HATr) were selected. To obtain A9 cells that contained a t(X;3) chromosome with an integrated neo gene, the microcell transfer step was repeated and doubly resistant cells were selected. G418r/HATr colonies arose at a frequently of 0.09 to 0.23 x 10(-6) per recipient cell. Of seven primary microcell hybrid clones, four yielded G418r/HATr clones at a detectable frequency (0.09 to 3.4 x 10(-6)) after a second round of microcell transfer. Doubly resistant cells were not observed after microcell chromosome transfers from three clones, presumably because the markers were on different chromosomes. The secondary G418r/HATr microcell hybrids contained at least one copy of the human t(X;3) chromosome and in situ hybridization with one of these clones confirmed the presence of a neo-tagged t(X;3) human chromosome. These results demonstrate that microcell chromosome transfer can be used to select chromosomes containing multiple markers.
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PMID:Introduction of new genetic markers on human chromosomes. 199 1


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