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HPRT Gene (hprt + gene)

Distribution by Scientific Domains

Life Sciences	80%

Selected Abstracts

Relative mutagenic potencies of several nucleoside analogs, alone or in drug pairs, at the HPRT and TK loci of human TK6 lymphoblastoid cells,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3-4 2007
Meghan M. Carter
Abstract Experiments were performed to investigate the impact of didanosine (ddI), lamivudine (3TC), and stavudine (d4T) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using a cell cloning assay for assessing the effects of individual nucleoside analogs (NRTIs)/drug combinations in human TK6 B-lymphoblastoid cells. Three-day treatments with 0, 33, 100, or 300 ,M ddI, 3TC, or ddI-3TC produced positive trends for increased HPRT and TK mutant frequencies. While dose-related trends were too small to reach significance after treatments with d4T or d4T-3TC, pairwise comparisons with control cells indicated that exposure to 100 ,M d4T or d4T-3TC caused significant elevations in HPRT mutants. Measurements of mutagenicity in cells exposed to d4T (or d4T-3TC) were complicated by the cytotoxicity of this NRTI. Enhanced increases in mutagenic responses to combined NRTI treatments, compared with single drug treatments, occurred as additive to synergistic effects in the HPRT gene of cells exposed to 100 ,M ddI-3TC or 100 ,M d4T-3TC, and in the TK gene of cells exposed to 100 or 300 ,M ddI-3TC. Comparisons of these data to mutagenicity studies of other NRTIs in the same system (Meng Q et al. [2000c]: Proc Natl Acad Sci USA 97:12667,126671; Torres SM et al. [2007]: Environ Mol Mutagen) indicate that the relative mutagenic potencies for all drugs tested to date are: AZT-ddI > ddI-3TC > AZT-3TC , AZT-3TC-ABC (abacavir) > AZT ,ddI > d4T-3TC > 3TC > d4T , ABC. These collective data suggest that all NRTIs with antiviral activity against HIV-1 may cause host cell DNA damage and mutations, and impose a cancer risk. Environ. Mol. Mutagen., 2007. © 2007 Wiley-Liss, Inc. [source]

Childhood hyperuricemia and acute renal failure resulting from a missense mutation in the HPRT gene

AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2002
Tarak Srivastava
Abstract A 6-year-old boy was determined to have partial hypoxanthine phosphoribosyl transferase (HPRT) enzyme deficiency without the phenotypic features of Lesch-Nyhan syndrome. He presented with recurrent acute renal failure (ARF) from hyperuricemia. Treatment with allopurinol prevented further attacks of renal failure. T lymphocyte cultures were used to sequence the HPRT cDNA and a novel single nucleotide substitution at codon 65 in exon 3 was found (193C,>,T, 65leu,>,phe). This mutation was confirmed by genomic DNA sequencing and was also detected in his heterozygous, asymptomatic mother and sister. Unlike the cells from patients with classic Lesch-Nyhan syndrome, the in vitro cultures of our patient's T-lymphocytes did not proliferate in the presence of purine analogue 6-thioguanine (TG). This report highlights the unusual occurrence of recurrent ARF in a child with partial HPRT enzyme deficiency. The absence of TG resistance in vitro with this mutation shows that even small alterations in enzyme activity in vivo can result in disease symptoms, in this instance, hyperuricemia sufficient to cause ARF. Atypical HPRT mutations should also be considered in cases of unusual renal failure, because correct diagnosis can allow appropriate treatment, as well as informed genetic counseling. © 2002 Wiley-Liss, Inc. [source]

Characterization of Hprt mutations in cDNA and genomic DNA of T-cell mutants from control and 1,3-butadiene-exposed male B6C3F1 mice and F344 rats

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2004
Quanxin Meng
Abstract A multiplex PCR procedure for analysis of genomic DNA mutations in the mouse hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene was developed and then used with other established methods for the coincident identification of large- and small-scale genetic alterations in the Hprt gene of mutant T-cell isolates propagated from sham- and 1,3-butadiene (BD)-exposed mice and rats. The spectra data for RT-PCR/cDNA analysis and multiplex PCR of genomic DNA from Hprt mutants were combined, and statistical analyses of the mutant fractions for the classes of mutations identified in control versus exposed animals were conducted. Under the assumption that the mutant fractions are distributed as Poisson variates, BD exposure of mice significantly increased the frequencies of (1) nearly all types of base substitutions; (2) single-base deletions and insertions; and (3) all subcategories of deletions. Significantly elevated fractions of G:C,C:G and A:T,T:A transversions in the Hprt gene of BD-exposed mice were consistent with the occurrence of these substitutions as the predominant ras gene mutations in multiple tumor types increased in incidence in carcinogenicity studies of BD in mice. BD exposure of rats produced significant increases in (1) base substitutions only at A:T base pairs; (2) single-base insertions; (3) complex mutations; and (4) deletions (mainly 5, partial and complete gene deletions). Future coincident analyses of large- and small-scale mutations in rodents exposed to specific BD metabolites should help identify species differences in the sources of deletion mutations and other types of mutations induced by BD exposures in mice versus rats. Environ. Mol. Mutagen. 43:75,92, 2004. © 2004 Wiley-Liss, Inc. [source]

Comparison of hprt and lacI mutant frequency with DNA adduct formation in N -hydroxy-2-acetylaminofluorene,treated Big Blue® rats,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2001
Tao Chen
Abstract N -Hydroxy-2-acetylaminofluorene (N -OH-AAF) is the proximate carcinogenic metabolite of the powerful rat liver carcinogen 2-acetylaminofluorene. In this study, transgenic Big Blue® rats were used to examine the relationship between in vivo mutagenicity and DNA adduct formation by N -OH-AAF in the target liver compared with that in nontarget tissues. Male rats were given one, two, or four doses of 25 mg N -OH-AAF/kg body weight by i.p. injection at 4-day intervals, and groups of treated and control rats were euthanized up to 10 weeks after beginning the dosing. Mutant frequencies were measured in the spleen lymphocyte hprt gene, and lacI mutant frequencies were determined in the liver and spleen lymphocytes. At 6 weeks after beginning the dosing, the hprt mutant frequency in spleen lymphocytes from the four-dose group was 16.5 × 10,6 compared with 3.2 × 10,6 in control animals. Also at 6 weeks, rats given one, two, or four doses of N- OH-AAF had lacI mutant frequencies in the liver of 97.6, 155.6, and 406.8 × 10,6, respectively, compared with a control frequency of 25.7 × 10,6; rats given four doses had lacI mutant frequencies in spleen lymphocytes of 55.8 × 10,6 compared with a control frequency of 20.4 × 10,6. Additional rats were evaluated for DNA adduct formation in the liver, spleen lymphocytes, and bone marrow by 32P-postlabeling. Adduct analysis was conducted 1 day after one, two, and four treatments with N -OH-AAF, 5 days after one treatment, and 9 days after two treatments. N- (Deoxyguanosin-8-yl)-2-aminofluorene was the major DNA adduct identified in all the tissues examined. Adduct concentrations increased with total dose to maximum values in samples taken 1 day after two doses, and remained essentially the same after four doses. In samples taken after four doses, adduct levels were 103, 28, and 7 fmol/,g of DNA in liver, spleen lymphocytes, and bone marrow, respectively. The results indicate that the extent of both DNA adduct formation and mutant induction correlates with the organ specificity for N- OH-AAF carcinogenesis in the rat. Environ. Mol. Mutagen. 37:195,202, 2001. Published 2001 Wiley-Liss, Inc. [source]

Severe gouty arthritis and mild neurologic symptoms due to F199C, a newly identified variant of the hypoxanthine guanine phosphoribosyltransferase

ARTHRITIS & RHEUMATISM, Issue 7 2009
Hang-Korng Ea
A deficiency in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity leads to overproduction of uric acid. According to the degree of enzymatic deficiency, a large spectrum of neurologic features can also be observed, ranging from mild or no neurologic involvement to complete Lesch-Nyhan disease. Herein, we describe a patient with hyperuricemia, juvenile-onset gouty arthritis, nephrolithiasis, and mild neurologic symptoms, attributed to a newly identified variant of the hprt gene, c.596T>G, resulting in the amino acid change p.F199C. Residual HPRT activity (8%) protected against severe neurologic involvement in this patient. Modeling of the mutated protein was used to predict the mechanisms that led to partial enzymatic activity. Careful neurologic examination is warranted in juvenile and middle-aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency. [source]