Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0451641 (urolithiasis)
 3,973 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular bases for hereditary cancer-prone diseases. 129 55

Adenine phosphoribosyltransferase (APRT) deficiency causes 2,8-dihydroxyadenine(DHA) urolithiasis and renal failure. Recently, two different common mutations were identified; one was APRT* J with a substitution of ACG for ATG at codon 136, called "Japanese-type", another was APRT* Q0 with TGA for TGG at codon 98. Approximately 98% of all Japanese patients with this disorder have been estimated to have these mutations APRT* J (approximately 80%) and/or APRT*Q0 (approximately 20%). We developed a diagnostic method to detect these genotypes. After gene amplification by PCR, target DNA was hybridized with a biotinylated specific probe in the presence of the non-labelled competitive probe on a dot-blotted membrane. To detect the APRT* J (or APRT* Q0) mutation, the biotinylated APRT* J (or APRT* Q0) probe and non-labelled normal probe for the same region were used as specific and competitive probes, respectively. After incubation at 60 degrees C for 30 min, the temperature was gradually decreased from 60 degrees C to 40 degrees C during 120 min, and then incubation was continued at 40 degrees C for 30 min. By using method, we were able to omit the posthybridization process, and the detecting signal was clear and highly specific. This method is useful for detecting point mutations in other genes.
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PMID:[Detection of the mutation responsible for adenine phosphoribosyltransferase deficiency among Japanese patients]. 130 10

Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis is a rapid and sensitive method to identify point mutations in a given sequence of genomic DNA. We tried to apply the PCR-SSCP to the diagnosis of adenine phosphoribosyltransferase (APRT) deficiency, which is an autosomal recessive hereditary disease leading to 2,8-dihydroxyadenine urolithiasis. Genomic APRT genes, with or without mutations, were amplified and labeled simultaneously with 32P-dCTP by PCR. When run in a 6% polyacrylamide gel containing 10% glycerol, two types of mutant genes, APRT*Q0 and APRT*J, gave bands clearly distinct from those of the respective normal APRT genes. Since heterozygotes as well as homozygotes for these mutant APRT genes can be detected in 2 days, PCR-SSCP should be a valuable method in the diagnosis of APRT deficiency and in screening a large population for APRT mutant genes.
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PMID:[Detection of mutant adenine phosphoribosyltransferase genes by polymerase chain reaction-single strand conformation polymorphism analysis]. 163 17

The post-initiation enhancing activities of the non-genotoxic agent NaHCO3 and the genotoxic agent N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) in combination with uracil-induced urolithiasis were investigated in a rat bladder carcinogenesis model. Animals were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks, and then 3% uracil was given for 3 weeks in the early (weeks 4-7), middle (weeks 8-11) or late (weeks 12-15) post-initiation phase. In addition, administration of 3% NaHCO3, 20 ppm EHBN or no chemical supplement was performed for the 13 weeks when the rats were not receiving BBN or uracil. NaHCO3 in sequential combination with early and middle stages uracil treatment strongly enhanced tumorigenesis in the urinary bladder, while EHBN treatment amplified lesion development at the middle stage only of uracil treatment. DNA synthesis and associated epithelial surface alterations observed by scanning electron microscopy tended to be increased in the NaHCO3 and EHBN groups without BBN initiation, independently of uracil treatment timing. The present results demonstrated that uracil-induced urolithiasis during the middle post-initiation phase is highly active in enhancing bladder tumor development under the influence of a promoter or carcinogen.
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PMID:Timing effects of uracil-induced urolithiasis on amplification of second-stage promotion in rat bladder carcinogenesis. 165 69

Adenine phosphoribosyltransferase (APRT) deficiency is a genetic disorder which causes 2,8-dihydroxy-adenine urolithiasis. The estimated incidence of heterozygosity in Caucasian and Japanese populations is 1%. Mutant alleles responsible for the disease have been classified as APRT*Q0 (type I) and APRT* (type II). In our previous study, we demonstrated in APRT*J a single common base change which accounts for 70% of the Japanese mutants. The present report describes the analysis of an APRT*Q0 mutation in Japanese subjects. Two nucleotide substitutions common to all seven affected alleles from four unrelated subjects (three homozygotes and a heterozygote) were identified: G----A at nucleotide position 1453 and C----T at 1456. The G----A altered the amino acid Trp98 to a stop codon. The C----T did not alter Ala99. These point mutations were demonstrated by sequence analysis of polymerase chain reaction (PCR)-amplified genomic DNA and cDNA. The G----A change at 1453 results in the elimination of a PflMI site in the APRT gene. PflMI digests, which were used to confirm the G----A transition, can be useful in screening for this specific mutation.
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PMID:A mutant allele common to the type I adenine phosphoribosyltransferase deficiency in Japanese subjects. 198 52

An accurate diagnosis of heterozygotes for autosomal recessive disorders with unknown mutations can be difficult. Using a unique phenomenon occurring in vivo, we designed a method for the diagnosis of heterozygotes for adenine phosphoribosyltransferase (APRT) deficiency which makes way for a qualitative distinction between normal and heterozygous subjects. We cultured peripheral blood mononuclear cells with 2,6-diaminopurine, an APRT-dependent cytotoxin, to search for in vivo mutational cells. Fifteen putative heterozygotes examined were found to possess such mutant cells at rather high frequencies; thus, a false negative diagnosis is unlikely. The analysis of genomic DNA in 82 resistant clones from two of the heterozygotes clarified that 64 (78%) had lost the germinally intact alleles. Thirteen members of APRT-deficient families were examined; eight proved to be heterozygotes. Among 425 individuals from two separate residential areas of Japan, two heterozygotes were found. The authenticity of the heterozygosity was validated by two separate methods for the two heterozygotes; hence, a false positive diagnosis can be ruled out. Our data showed a calculated heterozygote frequency of 0.47% (95% confidence limits; 0.05%-1.7%), a value compatible with that (1.2%) calculated from data concerning the incidence of 2,8-dihydroxyadenine urolithiasis. This novel genetic approach for identifying heterozygotes is now being tested to search for other enzyme deficiencies in humans.
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PMID:Diagnosis of heterozygous states for adenine phosphoribosyltransferase deficiency based on detection of in vivo somatic mutants in blood T cells: application to screening of heterozygotes. 199 41

Complete adenine phosphoribosyltransferase (APRT) deficiency causes 2,8-dihydroxyadenine urolithiasis. In previous reports, analysis of the kinetic properties of APRT from APRT-deficient Japanese subjects revealed strikingly similar abnormalities suggesting a distinct "Japanese-type" mutation. In this paper, we report studies of 11 APRT-deficient lymphoblast cell lines. Nucleotide sequence analysis of APRT genomic DNA from WR2, a Japanese-type homozygote, identified a T to C substitution in exon 5, giving rise to the substitution of threonine for methionine at position 136. RNase mapping analysis confirmed this mutation in WR2 and revealed that six other Japanese-type homozygotes carry the same mutation on at least one allele. The remaining Japanese subject, who does not express the Japanese-type phenotype, did not demonstrate this mutation. Southern blot analysis showed that all seven Japanese-type subjects were confined to one TaqI restriction fragment length polymorphism (RFLP) haplotype. These studies provide direct evidence for the nature of the mutation in the Japanese-type APRT deficiency.
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PMID:Human adenine phosphoribosyltransferase deficiency. Demonstration of a single mutant allele common to the Japanese. 334 50

We analyzed DNA from six Japanese patients with adenine phosphoribosyltransferase (APRT) deficiency who developed 2,8-dihydroxyadenine (DHA) urolithiasis. These six patients were selected for DNA analysis since they were expected to possess allele(s) with mutations other than two known abnormalities, i.e. a missense mutation at codon 136 (APRT*J allele) and a nonsense mutation at codon 98. In three of the six patients an insert of four bases CCGA was detected in exon 3 by sequencing clones obtained from the genomic DNA. In two of the three patients, both of the two alleles had this mutation (homozygotes) while the other patient had the APRT*J allele in addition to the allele with the 4-base insertion. To search for mutations other than the above three defined germline mutations, we amplified a genomic DNA segment including all the 5 exons of the APRT gene by PCR and cloned it into a plasmid. After selecting recombinant plasmids containing neither of the three defined mutations, we sequenced the entire APRT exons and introns. Abnormalities were found in neither the coding regions nor the exon-intron junctions. Disease-related mutations in these mutant alleles may exist in either 5' or 3' flanking sequences and remain to be elucidated.
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PMID:Detection of the three common mutations of adeninephosphoribosyltransferase deficiency among Japanese. 775 7

Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis is a rapid and sensitive method used to identify point mutations in a given sequence of genomic DNA. We applied this method to the diagnosis of adenine phosphoribosyltransferase (APRT) deficiency, which is an autosomal recessive hereditary disease leading to 2,8-dihydroxyadenine urolithiasis. Genomic APRT genes were amplified and labeled simultaneously with [alpha-32P]dCTP (cytidine triphosphate) by PCR. When run in a 6% polyacrylamide gel containing 10% glycerol, two types of mutant genes-APRT*QO and APRT*J-gave bands clearly distinct from those of the equivalent normal APRT genes. Using this method we diagnosed both homozygotes and heterozygotes for defective APRT genes. On screening 80 Japanese individuals for polymorphism or mutations by PCR-SSCP we did not find any alterations leading to a false positive diagnosis. These findings suggest that PCR-SSCP, in addition to being rapid and sensitive, is a useful diagnostic method which is highly specific in detecting mutant APRT genes in the Japanese population.
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PMID:Application of polymerase chain reaction-single strand conformation polymorphism analysis to the diagnosis and screening of adenine phosphoribosyltransferase deficiency. 850 53

Proteus mirabilis, associated with complicated urinary tract infection, expresses mannose-resistant/Proteus-like (MR/P) fimbriae. Expression of these surface structures, which mediate haemagglutination and have a demonstrated role in virulence, undergoes phase variation. By DNA sequence analysis, a 252 bp invertible element was found in the intergenic region between mrpl, the putative site-specific recombinase gene, and mrpA, the primary structural subunit gene. The invertible segment is flanked by identical 21 bp inverted repeats and the presumptive half-sites for recombinase binding show homology to those recognized by FimB and FimE encoded by the Escherichia coli fim (Type 1 fimbriae) gene cluster. When amplified by the polymerase chain reaction (PCR) from static broth cultures expressing MR/P fimbriae, the switch region was found in both ON and OFF positions. When PCR was used to amplify agar cultures which do not express the fimbriae, the switch region was OFF only. A canonical sigma 70 promoter inside the invertible element drives the transcription of mrpA when in the ON position; in the OFF position it is directed away from mrpA but does not appear to drive expression of mrpI. The mrpI gene was able to confer inversion of the mrp switch region in trans from both ON to OFF and OFF to ON. To examine the position of the switch in vivo, urine, bladder, and kidneys from mice transurethrally infected with P. mirabilis were used to prepare template DNA for PCR amplification. In the absence of urolithiasis (urease-mediated stone formation), the switch was found 100% in the ON position, a condition never observed following in vitro culture. We conclude that MR/P phase variation is regulated at the transcriptional level by the action of MrpI on an invertible element and that there is strong selective pressure for the expression of MR/P fimbriae in vivo.
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PMID:In vivo phase variation of MR/P fimbrial gene expression in Proteus mirabilis infecting the urinary tract. 907 37


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