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)

To investigate the possible contribution of intragenic differentially methylated cytosines to X-linked gene expression, we examined DNA-protein interactions in a region in intron 3 of the human hypoxanthine phosphoribosyltransferase gene which contains at least one HpaII site methylated specifically on the active X. In vitro DNase I footprinting experiments using unmethylated DNA and HeLa nuclear extract identified three footprints (I-III). Footprints I and III flank an Alu repeat containing the HpaII site(s), one of which is contained within footprint II. Although methylation of the HpaII site had no effect on footprint II binding interactions, methylation of nearby CpGs substantially reduced the formation of three of the specific DNA-protein complexes binding to footprint II in mobility shift assays. Additionally, an A+T rich region immediately 5' to the HpaII-containing Alu repeat was found to bind specifically to nuclear matrices in vitro. We suggest that differential methylation of CpGs may affect the binding of regulatory proteins in vivo, and that interactions between the footprint proteins and those binding to the matrix attachment region may be involved in controlling X-linked Hprt expression.
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PMID:Intragenic matrix attachment and DNA-protein interactions in the human X-linked Hprt gene. 757 42

An X-linked clone encoding exons 4-9 of the hypoxanthine phosphoribosyltransferase (HPRT) gene was isolated from a kangaroo (Macropus robustus: Marsupialia) lambda EMBL4 genomic library. Sequence similarity between the kangaroo and eutherian HPRT coding sequences was high; however, intron sizes varied significantly between the kangaroo and other eutherian species. HpaII and HhaI sites in the body of the gene were generally hypermethylated in vivo on the active, relative to the inactive X, with sites within intron 3 showing essentially complete correspondence of activity with methylation and inactivity with unmethylation. At approximately 5 kb downstream from the gene, a switch to unmethylation of active X-linked sites occurred. This switch occurred within a cluster of HpaII and HhaI sites that may represent a CG island associated with a subsequent gene.
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PMID:Isolation of a clone partially encoding hill kangaroo X-linked hypoxanthine phosphoribosyltransferase: sex differences in methylation in the body of the gene. 768 49

The thoraco-abdominal syndrome (TAS) presents a closure defect confined to the ventral midline, manifested as ventral hernia of various degrees in all affected individuals and antero-lateral diaphragmatic defect manifested almost exclusively in affected males. The syndrome is inherited as an X-linked dominant trait affecting blastogenesis (XLB mutation). We studied 27 members of the TAS family for linkage on the X chromosome. The best lod score of 5.5 at theta 0.04 was found for the HPRT locus on Xq26.1. A multilocus lod score of 12.4 was observed when the linkage analysis utilized additional markers in Xq25-26.
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PMID:Linkage localization of the thoraco-abdominal syndrome (TAS) gene to Xq25-26. 790 97

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked gigantism syndrome characterized primarily by a coarse facies and somatic overgrowth which we have observed to be associated with an increased risk for embryonal tumors. Genetic linkage analysis for two SGBS kindreds in which X linked dominant inheritance was observed has been conducted for the X chromosome. The closest linkage to SGBS was observed for the Xq26 locus HPRT (Z max = 7.45, theta max = 0.00). SGBS-Xq marker recombinations map the disease locus to the DXS425-DXS1123 interval on Xq25-q27. This maps the disease locus to a region known to contain a previously characterized chromosomal translocation breakpoint found in a young girl with somatic overgrowth. This observation may have implications for the cloning of the SGBS gene.
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PMID:Mapping of Simpson-Golabi-Behmel syndrome to Xq25-q27. 790 48

Clonal haemopoiesis has previously been demonstrated in some 30% of patients in remission of acute myeloid leukaemia (AML). Whilst a 'clonal remission' in many such patients may represent a skewed X-chromosome inactivation pattern in haemopoietic cells, its relationship to an underlying preleukaemic state remains uncertain. We therefore analysed the clonal status of 48 female patients in remission of AML using X-chromosome linked restriction fragment length polymorphisms (RFLPs) within the X-linked PGK and HPRT genes and the DXS255 (M27 beta) locus, and carried out in conjunction a detailed study of the morphological and karyotypic features of the patients' bone marrows. During remission, 35 patients (73%) with AML demonstrated nonclonal haemopoiesis, and their bone marrows were morphologically normal. Remission haemopoietic tissue in nine cases (19%) showed a skewed X-chromosome inactivation pattern and remission bone marrows in these patients had features of trilineage myelodysplasia (TMDS), with seven having similar features at presentation. Analysis of constitutional DNA showed a non-clonal pattern in seven of these patients, but was unsuccessful in two cases. These nine patients with post-chemotherapy TMDS were considered to have true clonal haemopoiesis. Four patients (8%) with a skewed X-chromosome inactivation pattern had normal remission bone marrows. Analysis of constitutional DNA showed a skewed pattern in two of these patients, but was unsuccessful in two cases. Cytogenetic investigation during remission in the nine patients with TMDS showed a normal karyotype in four cases and the acquisition of new karyotypic abnormalities in three cases. In contrast, 10 female patients in remission of de novo acute lymphoblastic leukaemia (ALL) were shown to have non-clonal haemopoiesis. We conclude that the majority of patients with AML who achieve remission after cytoreductive chemotherapy have non-clonal haemopoiesis, and when clonal remissions are observed these are commonly associated with the development of trilineage myelodysplasia in the bone marrow, with or without karyotypic abnormalities. True clonal remission in association with morphologically normal haemopoiesis is a rare entity, the significance and frequency of which remain uncertain.
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PMID:Clonal remissions in acute myeloid leukaemia are commonly associated with features of trilineage myelodysplasia during remission. 791 32

Inactive-X-chromosome genes in mammalian females have methylated CpG islands. We have questioned whether there are variable levels of cytosine methylation at different CpG sites within the island that might indicate the presence of primary sites of methylation which may be critical for the maintenance of gene repression and candidate sites for the initiation of inactivation. To address these questions, we have analyzed the methylation patterns of 32 CpG sites of the X-linked hypoxanthine phosphoribosyltransferase (Hprt) gene on the active and inactive X chromosomes of mouse tissues and cell lines, using genomic sequencing of bisulfite-treated genomic DNA. Cytosine is deaminated by bisulfite, but methylcytosine is not affected. Cell lines that were heterozygous for the Hprt deletion mutation (Hprtb-m3) and a functional Hprt allele were selected with 6-thioguanine. The resulting cell populations uniformly carry the intact Hprt allele on the inactive X chromosome. The methylation of these CpG sites was determined either by the direct sequence analysis of bisulfite-treated and amplified DNA or by the sequence analysis of clones derived from the amplified DNA. No CpG methylation was detected on the active Hprt genes from either males or the active X chromosome of females. On average, 22 CpGs were methylated in the other 50% of female DNA, and the level of methylation at individual sites varied from 42 to 100%. Analysis of the inactive Hprt gene in two cell lines showed that averages of 14 and 18 CpGs were methylated and that the frequency of methylation at 32 individual sites ranged from 3 to 100%. The highest frequency of methylation in cell lines coincided with the sequences flanking transcription initiation sites. These results suggest that methylation patterns are heterogeneous within a tissue and even in clonal cell populations and that specific subsets of CpG sites sustain high methylation frequencies which may be critical for the maintenance of X-chromosome inactivation. The bisulfite method identified which CpG sites were methylated on the inactive X chromosome, and it provided a quantitative estimate of the frequency of methylation of these sites in genomic DNA.
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PMID:CpG island promoter region methylation patterns of the inactive-X-chromosome hypoxanthine phosphoribosyltransferase (Hprt) gene. 796 37

To test whether chromosomal instability is associated with familial Alzheimer's disease, we examined breakage on X chromosomes of fibroblasts derived from patients with familial Alzheimer's disease, using gene cotransfer methodology. The X chromosome is a convenient target for analyzing DNA breakage because of its numerous markers and ease of selection in rodent-human hybrid cells. Patients with familial Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a significantly lower cotransfer of the X-linked glucose-6-phosphate dehydrogenase (G6PD) gene with the selected HPRT gene in hybrid cells, indicating breakage between the markers. Lower cotransfer of the more distant X-linked gene, MIC-2, was statistically significant in this kindred, but not in other patients with familial Alzheimer's disease. The distance between MIC2 and HPRT is sixfold to ninefold greater than that between HPRT and G6PD, suggesting that there may be a "hot spot" for breakage in the latter interval on the X chromosome of patients with familial Alzheimer's disease. The somatic cell hybrid model provides insights into underlying mechanisms for chromosomal breakage induced by the Alzheimer defect. A hypothesis implicating a candidate gene, C1-THF synthase, in the generation of chromosome instability in the pathogenesis of familial Alzheimer's disease, is presented.
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PMID:Chromosomal fragility associated with familial Alzheimer's disease. 805 55

The basis of a previously observed difference in the level of contribution of hypoxanthine phosphoribosyltransferase-deficient cells between the haematopoietic and non-haematopoietic tissues of chimaeric and heterozygous mice has been clarified by studying two populations of female mice that differ only in that one is heterozygous for a null allele at the hprt locus and the other is wild type at this locus. Both populations are heterozygous for an electrophoretic variant allele at the X-linked Pgk-1 locus, so that X-chromosome inactivation generates cells expressing different isozymes of phosphoglycerate kinase which can be assayed to monitor cell selection. The results show that hypoxanthine phosphoribosyltransferase deficiency itself, rather than an effect of another X-linked gene, causes a reduced level of contribution to haematopoietic tissues. Further, the extent of the depletion increases significantly with age, and this effect is due to a progressive reduction in the level of contribution to haematopoietic tissues rather than to an increase in the level of contribution to non-haematopoietic tissues.
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PMID:Age-dependent selection against hypoxanthine phosphoribosyl transferase-deficient cells in mouse haematopoiesis. 807 22

Analysis of X-chromosome inactivation patterns in females has been used to assess clonality of various tumours and for prenatal diagnosis of X-linked disorders. Studies with these methods in acute myeloid leukaemia suggest that a significant proportion of cases have clonal remissions (ie, persistence of the malignant clone), which may represent return to a preleukaemic state. We therefore analysed X-chromosome inactivation patterns with differential methylation patterns of heterozygotes for three DNA probes, HPRT, PGK, and M27 beta, in leukaemic patients and normal controls. As expected, blast cells from 67 of 68 analysable samples (99%) were monoclonal or had a skewed X-inactivation pattern. A skewed pattern in remission was also found in 26 of 77 patients (34%), proportion only slightly greater than control (16/75, 21%). In 7 of 10 patients with a skewed pattern in myeloid cells there was similar skewing in the T cells, which is compatible with the concept of a constitutively skewed X-chromosome inactivation pattern of haemopoietic cells in these patients. Our study illustrates the difficulty of interpreting clonality in individual tumour samples and emphasises the importance of comparisons with non-malignant tissue of the same cell type from that individual and from normal control populations.
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PMID:Frequency of clonal remission in acute myeloid leukaemia. 809 44

Clonality analysis, by means of polymorphisms of X-linked genes and their methylation patterns, was performed in 41 female patients with various types of refractory anemia. Bone marrow cells, peripheral blood cells, and granulocytic and lymphocytic fractions were analysed by Southern blotting with PGK, HPRT, and M27 beta probes. Clonal hematopoiesis was evidenced in 8 of 19 patients with aplastic anemia, 4 of 6 patients with RA or RARS, 3 of 7 patients with PNH, and 5 of 9 patients whose hematological characteristics did not meet the criteria of either of these entities. For aplastic anemia, clonal hematopoiesis was demonstrated in higher frequency in the patients who had longer history after diagnosis. In refractory anemia, as a whole, no clear correlation was observed between existence of clonal hematopoiesis and morphological characteristics of hematological cells.
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PMID:[Clonality in refractory anemia]. 809 42


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