Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.7 (adenine phosphoribosyltransferase)
 692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,8-Dihydroxyadenine urolithiasis is an inherited disorder caused by adenine phosphoribosyltransferase deficiency. A fast, simple, sensitive and selective capillary zone electrophoretic method for diagnosis of 2,8-dihydroxyadenine urolithiasis in adenine phosphoribosyltransferase deficiency is described. The method is based on direct measurement of 2,8-dihydroxyadenine in untreated urine in phosphate buffer at pH 3.0 within 8 min. Under the given separation conditions 2,8-dihydroxyadenine is very well separated from other purine and pyrimidine substances and presents characteristic UV spectra which enable identification in case of doubt. The urine samples containing pathological 2,8-dihydroxyadenine could be successfully analysed in levels approaching those relevant for bioanalytical applications. The reliability of the method presented for screening of patients with adenine phosphoribosyltransferase deficiency is demonstrated on a urine sample of a patient with the defect who was already treated with allopurinol at the time of obtaining the sample. No interfering substances were found in 50 urine samples from healthy infants under the analytical condition described.
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PMID:A fast and simple screening method for detection of 2,8-dihydroxyadenine urolithiasis by capillary zone electrophoresis. 864 18

Adenine phosphoribosyltransferase deficiency is an autosomal recessive purine enzyme defect that causes urolithiasis and, in severe cases, renal failure. Most homozygotes with this disorder were identified by analyses of excreted or surgically removed urinary stones, but some were identified only because they were family members of symptomatic individuals. We report here the detection of adenine phosphoribosyltransferase deficiency in two cases by routine analysis of urinary sediments. 2,8-Dihydroxyadenine-like spherical crystals were observed in the urinary sediment, and a diagnosis of homozygous adenine phosphoribosyltransferase deficiency was confirmed by cellular and molecular methods. A molecular diagnostic system using the polymerase-chain reaction and single-strand conformational polymorphism analysis proved to be a rapid and sensitive method to identify the APRT*J allele, a common mutant allele among the Japanese people. These methods will facilitate identification of symptomatic and asymptomatic individuals with homozygous adenine phosphoribosyltransferase deficiency.
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PMID:Adenine phosphoribosyltransferase deficiency identified by urinary sediment analysis: cellular and molecular confirmation. 882 2

Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.
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PMID:Mice with adenine phosphoribosyltransferase deficiency develop fatal 2,8-dihydroxyadenine lithiasis. 886 50

In vivo somatic mutations have been detected at several human loci by using clonal cultures of peripheral blood T-cells. It has not been fully understood whether or not the somatic mutations in T-cells are similar to those of other cell types. To address this issue, we cloned, from human peripheral blood, T- and B-cells with mutations at an autosomal adenine phosphoribosyltransferase (APRT) locus. For the efficient detection of somatic mutations at the APRT locus, a blood sample from a human individual heterozygous for germline APRT deficiency was used. T- and B-cells deficient in APRT enzyme activity were cloned from peripheral blood mononuclear cells using a selecting agent, 2,6-diaminopurine. The APRT-deficient mutant frequencies were on the order of 10(-4) in both T- and B-cells. The single-strand conformation polymorphism analysis of the APRT DNA of mutant B-cell clones suggested that the molecular mechanisms leading to the APRT deficiency in B-cells were similar to those in T-cells. Our observations suggest that both the frequency and the mode of in vivo somatic mutations occurring spontaneously at general autosomal loci in B-cells are similar to those in T-cells.
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PMID:Similarity of in vivo somatic mutations at an autosomal adenine phosphoribosyltransferase locus between T- and B-cells in human peripheral blood. 887 86

The incidence of adenine phosphoribosyltransferase (APRT) deficiency is higher among Japanese nationals than among other ethnic groups, and the most common mutation (APRT*J, ATG to ACG mutation at codon 136) accounts for 68% of the disease-causing genes among Japanese. To investigate the origin of these mutations, we studied the geographical distribution of the mutant genes in Japan. The APRT*J mutation is distributed nearly uniformly in the four main islands of Japan and Okinawa, suggesting a very early origin. The products of PCR amplification between positions 2344 and 2750 of the genomic APRT sequence were examined by SSCP analysis in random blood samples from Japanese, Korean, and Taiwanese nationals. Among 955 random Japanese blood samples, 7 (0.73%) were heterozygous for the APRT*J mutation, giving a calculated heterozygote frequency of 1.1% among Japanese for the entire APRT deficiency. None of 231 Taiwanese samples contained heterozygotes for the APRT*J mutation, while 2 (0.53%) of 356 Korean samples were heterozygous. In addition to the APRT*J sequence, a total of five variant sequences was found. Sequencing one variant revealed a base substitution in intron 4, suggesting therefore that they are harmless mutations. Since the APRT*J mutation is present in Koreans and Okinawans who share ancestors only before the Yayoi era (third century BC to third century AD), the origin of the APRT*J mutation predates 300 BC.
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PMID:The origin of the most common mutation of adenine phosphoribosyltransferase among Japanese goes back to a prehistoric era. 888 82

We determined the nature of mutations occurring at the autosomal APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. The analysis of mutations that result in APRT deficiency in a mismatch-repair-deficient strain of DLD-1 heterozygous for this locus enabled us to measure the rate of loss of the wild-type gene through deletion, recombination, or gene conversion as well as the rate of point mutation. The overall rate of mutation at the APRT locus in DLD-1 was elevated 100-fold compared with the mismatch-repair-proficient colorectal carcinoma cell line SW620. Loss of heterozygosity (LOH) at APRT accounted for only 4 to 9% of mutant strains derived from DLD-1, indicating a rate for these types of events of 4 x 10(-7) to 9 x 10(-7). In SW620 the rate of LOH at APRT was about 10-fold higher. LOH was not found at polymorphic markers within the same chromosome subband as APRT, indicating that only a limited portion of the chromosome was affected by these alterations. Chromosome painting of SWS620 mutants revealed that the loss of APRT occurred together with a substantial portion of the long arm of chromosome 16. Differences in the nature of base substitutions at APRT (e.g., the proportion of mutations resulting from transitions or transversions) in these tumor cell lines were also detected. There was also an important similarity---the presence of a mutant APRT gene with multiple base substitutions that may be the result of some sort of error-prone DNA synthesis.
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PMID:Loss of heterozygosity and base substitution at the APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. 888 80

Complete hypoxanthine-guanine phosphoribosyl-transferase (HPRT) deficiency in humans results in the Lesch-Nyhan syndrome which is characterized, among other features, by compulsive self-injurious behavior. HPRT-deficient mice generated using mouse embryonic stem cells exhibit none of the behavioral symptoms associated with the Lesch-Nyhan syndrome. Administration of drugs that inhibit adenine phosphoribosyltransferase (APRT) in HPRT-deficient mice has produced the suggestion that deficiency of APRT in combination with HPRT-deficiency in mice may lead to self-mutilation behavior [C.L. Wu and D.W. Melton (1993) Nature Genet. 3, 235-240]. To test this proposition, we bred HPRT-APRT-deficient mice. Although the doubly-deficient mice excrete adenine and its highly insoluble derivative, 2,8-dihydroxyadenine, which are also associated with human APRT deficiency, additional abnormalities or any self-injurious behavior were not detected. Thus, APRT-HPRT-deficient mice, which are devoid of any purine salvage pathways, show no novel phenotype and are not a model for the behavioral abnormalities associated with the Lesch-Nyhan syndrome as previously suggested.
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PMID:HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome. 889 95

Both germline and somatic mutations are known to affect phenotypes of human cells in vivo. In previous studies, we cloned mutant peripheral blood T cells from germline heterozygous humans for adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7) deficiency and found that approximately 1.3 x 10-4 peripheral T cells had undergone in vivo somatic mutations. Loss of heterozygosity (LOH) was the major cause of the mutations at the APRT locus since approximately 80% of the mutant T cell clones exhibited loss of normal alleles. In the present study, we identified three heterozygous individuals for APRT deficiency (representing two separate families), in whom none of the somatic mutant cells exhibited LOH at the APRT locus. The germline mutant APRT alleles of these heterozygotes from two unrelated families had the same gross DNA abnormalities detectable by Southern blotting. None of the germline mutant APRT alleles so far reported had such gross DNA abnormalities. The data suggest that the germline mutation unique to these heterozygous individuals is associated with the abrogation of LOH in somatic cells. The absence of LOH at a different locus has already been reported in vitro in an established cell line but the present study describes the first such event in vivo in human individuals.
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PMID:Intervention of somatic mutational events in vivo by a germline defect at the adenine phosphoribosyltransferase locus. 904 14

A 30-year-old woman was admitted to our hospital because of recurrent ureterolithiasis. She was suspected of having adenine phosphoribosyltransferase (APRT) deficiency based on the presence of 2,8-dihydroxyadenine (DHA) crystals in her urinary sediment, infrared spectrophotometric analysis of the excreted stone, and then the definitive diagnosis by gene analysis. A pedigree study indicated only a slight possibility of this disease in the family. From these results, we consider that urinary sediment and stone analysis should be used for screening while gene analysis should be employed for definitive diagnosis of APRT deficiency, so that the complications of this condition can be prevented.
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PMID:Partial adenine phosphoribosyltransferase deficiency detected by ureterolithiasis. 951 Apr 4

In humans, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency can manifest as nephrolithiasis, interstitial nephritis, and chronic renal failure. APRT catalyzes synthesis of AMP from adenine and 5-phosphoribosyl-1-pyrophosphate. In the absence of APRT, 2,8-dihydroxyadenine (DHA) is produced from adenine by xanthine dehydrogenase (XDH) and can precipitate in the renal interstitium, resulting in kidney disease. Treatment with allopurinol controls formation of DHA stones by inhibiting XDH activity. Kidney disease in APRT-deficient mice resembles that seen in humans. By age 12 wk, APRT-deficient male mice are, on average, mildly anemic and smaller than normal males. They have extensive renal interstitial damage (assessed by image analysis) and elevated blood urea nitrogen (BUN), and their creatinine clearance rates, which measure excretion of infused creatinine as an estimate of glomerular filtration rate (GFR), are about half that of wild-type males. APRT-deficient males treated with allopurinol in the drinking water had normal BUN and less extensive visible renal damage, but creatinine clearance remained low. Throughout their lifespans, homozygous null female mice manifested significantly less renal damage than homozygous null males of the same age. APRT-deficient females showed no significant impairment of GFR at age 12 wk. Consequences of APRT deficiency in male mice are more pronounced than in females, possibly due to differences in rates of adenine or DHA synthesis or to sex-determined responses of the kidneys.
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PMID:Chronic renal failure in a mouse model of human adenine phosphoribosyltransferase deficiency. 968 17


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