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)

Lesch-Nyhan syndrome involves disorders of both purine and dopamine metabolism. Neonatal lesioning of dopaminergic neurons with 6-hydroxydopamine (6-OHDA) has been proposed as a rodent model of the dopamine deficiency in this childhood disorder. In the present studies, the functional interaction between purines and dopamine was examined in adult rats which received 6-OHDA lesions either as neonates or as adults. Even though dopamine levels were decreased by at least 92%, both neonatal- and adult-6-OHDA-lesioned rats had normal hypoxanthine-guanine phosphoribosyltransferase function and purine nucleotide levels (adenosine, ADP, ATP and AMP), indicating that hypoxanthine-guanine phosphoribosyltransferase is not localized only to dopaminergic neurons in striatum. However, the 6-OHDA-lesioned animals were supersensitive to the locomotor activating effects of the adenosine antagonist, theophylline, with the response being greater in adult-6-OHDA-lesioned rats. This effect was presynaptic to dopaminergic neurons as indicated by alpha-methyltyrosine blockade of the theophylline response and its reinstatement by L-dopa. The presynaptic nature of this action of theophylline was supported further by a lack of interaction between theophylline and the direct acting D1- and D2-dopamine agonists, SKF-38393 and LY-171555, respectively. After systemic administration of SKF-38393 or L-dopa, central microinjection of the adenosine agonists, 2-chloroadenosine or 5'-N-ethylcarboxamide adenosine, were effective in preventing self mutilation induced by these dopamine agonists in neonatally lesioned rats. Relative potencies of the adenosine agonists for A1 and A2-adenosine receptors suggested involvement of an A2-adenosine receptor in this action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine. 312 93

The concentration of hypoxanthine-guanine phosphoribosyltransferase (HPRT) cross-reacting material (CRM) was determined in haemolysates and/or lymphoblast lysates from nine patients with complete or partial deficiency of HPRT activity. Two of the patients had the fully developed Lesch-Nyhan syndrome and although they had undetectable HPRT activity, small amounts of CRM were found. HPRT-specific mRNA was not detected in lymphoblast lysates from one of these patients, while lysates from the other had a much reduced concentration. Samples from three patients with less than 0.1% of normal HPRT activity but with minor or no neurological manifestations were also found to contain small amounts of CRM. The other four patients whose HPRT activities ranged from 3 to 10% of normal were found to have CRM concentrations which varied from 26 to 100% of normal. In one patient with a partial deficiency the Km for 5-phospho-alpha-D-ribosyl-1-pyrophosphate was five times normal.
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PMID:Biochemical basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in nine families. 314 64

We have determined the molecular basis for hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in a patient, J.H., with Lesch-Nyhan syndrome. Radioimmunoassay of lysates of erythrocytes or cultured B-lymphoblasts showed that this patient had no detectable HPRT enzyme activity or HPRT protein. HPRT-specific mRNA levels were normal by Northern analysis. We created a cDNA library from mRNA isolated from cultured lymphoblasts derived from this patient. Nucleotide sequencing of full-length HPRT cDNA clones revealed a single nucleotide (nt) substitution: a T-to-A transversion at nt 389. We have designated this variant HPRTMidland. The predicted amino acid (aa) substitution in HPRTMidland is a valine to aspartic acid at aa 130. This substitution is within 2 aa of the amino acid substitution in a previously defined HPRT variant, HPRTAnn Arbor. Both mutations are within a highly conserved sequence in the putative 5-phosphoribosyl-1-pyrophosphate-binding domain. The amino acid substitution in HPRTMidland causes a significant perturbation in the predicted secondary structure of this region. The HPRTMidland mutation affects a different domain of HPRT than the HPRTFlint mutation located at 167 nt away.
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PMID:Human hypoxanthine-guanine phosphoribosyltransferase: a single nucleotide substitution in cDNA clones isolated from a patient with Lesch-Nyhan syndrome (HPRTMidland). 326 98

Molecular analysis of four unrelated patients with Lesch-Nyhan (L-N) syndrome was performed. All four cases had typical clinical features of L-N syndrome, and the activities of hypoxanthine-guanine phosphoribosyltransferase (HPRT) were absent. No structural gene abnormalities were found by Southern blot analysis in all cases, and a decrease of HPRT mRNA was not detected by dot blot analysis in two of the four cases. However, HPRT enzyme proteins were detected by Western blot analysis in all cases. Our results showed that the production of immunologically reactive but enzymatically inactive mutant HPRT protein was pathogenic for all four patients.
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PMID:Molecular analysis of Lesch-Nyhan syndrome found in Japan. 341 75

Genomic deoxyribonucleic acid (DNA) was isolated from six hemizygotes and five heterozygotes from unrelated families exhibiting the full clinical spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. The DNA was digested with the restriction endonucleases, Bam H1, Pst 1 and Taq 1, previously found to be useful in demonstrating restriction fragment length polymorphism (RFLP) at the HPRT locus of the X-chromosome. DNA blotting experiments using a full length HPRT-cDNA probe, have revealed RFLPs in three families which may prove useful for the diagnosis of HPRT deficiency and the determination of heterozygosity. Total ribonucleic acid (RNA) was also extracted from our 11 subjects and analysed by Northern blotting for the presence of HPRT-messenger (mRNA). Apparently normal HPRT-mRNA was demonstrated in all the hemizygotes and heterozygotes for partial HPRT deficiency. In the families with complete HPRT deficiency (Lesch-Nyhan syndrome), the heterozygotes had normal HPRT-mRNA. However, one hemizygote had a complete absence of message for HPRT, while the other hemizygote had considerably reduced amounts of this message.
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PMID:Molecular studies of hypoxanthine-guanine phosphoribosyltransferase mutations in six Australian families. 343 20

Defective ecotropic and amphotropic retroviral vectors containing the cDNA for human hypoxanthine phosphoribosyltransferase (HPRT) were developed for efficient gene transfer and high-level cellular expression of HPRT. Helper cell clones which produced a high viral titer were generated by a simplified method which minimizes cell culture. We used the pZIP-NeoSV(X) vector containing a human hprt cDNA. Viral titers (1 X 10(3) to 5 X 10(4)/ml) of defective SVX HPRT B, a vector containing both the hprt and neo genes, were increased 3- to 10-fold by cocultivation of the ecotropic psi 2 and amphotropic PA-12 helper cells. Higher viral titers (8 X 10(5) to 7.5 X 10(6] were obtained when nonproducer NIH 3T3 cells or psi 2 cells carrying a single copy of SVX HPRT B were either transfected or infected by Moloney leukemia virus. The SVX HPRT B defective virus partially corrected the HPRT deficiency (4 to 56% of normal) of cultured rodent and human Lesch-Nyhan cells. However, instability of HPRT expression was detected in several infected clones. In these unstable variants, both retention and loss of the SVX HPRT B sequences were observed. In the former category, cells which became HPRT- (6-thioguanine resistant [6TGr]) also became G418s, indicative of a cis-acting down regulation of expression. Both hypoxanthine-aminopterin-thymidine resistance (HATr) and G418r could be regained by counterselection in hypoxanthine-aminopterin-thymidine. In vitro mouse bone marrow experiments indicated low-level expression of the neo gene in in vitro CFU assays. Individual CFU were isolated and pooled, and the human hprt gene was shown to be expressed. These studies demonstrated the applicability of vectors like SVX HPRT B for high-titer production of defective retroviruses required for hematopoietic gene transfer and expression.
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PMID:Construction of a defective retrovirus containing the human hypoxanthine phosphoribosyltransferase cDNA and its expression in cultured cells and mouse bone marrow. 346 9

Lesch-Nyhan syndrome results from a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). It is manifest by behavioral abnormalities, including self-mutilation, and evidence of abnormal 3,4-dihydroxyphenylethylamine (dopamine) metabolism. To assess whether an HPRT deficiency in a dopaminergic cell can adversely affect dopamine metabolism in that cell, dopamine metabolism was examined in HPRT-deficient variants of PC12 pheochromocytoma cells and in cells that had regained HPRT activity by virtue of transformation with a recombinant retrovirus containing the human gene for HPRT. There was no correlation between HPRT activity and endogenous dopamine levels, dopamine uptake, dopamine release, or monoamine oxidase activity. Transformation with the HPRT retrovirus did not adversely affect dopamine metabolism.
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PMID:Dopamine metabolism in hypoxanthine-guanine phosphoribosyltransferase-deficient variants of PC12 cells. 351 67

Many mutations leading to human disease are the result of single DNA base pair changes that cannot be identified by Southern analysis. This has prompted the development of alternative assays for point mutation detection. The recently described ribonuclease A cleavage procedure, with a polyuridylic acid-paper affinity chromatography step, has been used to identify the mutational lesions in the hypoxanthine phosphoribosyltransferase (HPRT) messenger RNAs of patients with Lesch-Nyhan syndrome. Distinctive ribonuclease A cleavage patterns were identified in messenger RNA from 5 of 14 Lesch-Nyhan patients who were chosen because no HPRT Southern or Northern blotting pattern changes had been found. This approach now allows HPRT mutation detection in 50 percent of the cases of Lesch-Nyhan syndrome. The polyuridylic acid-paper affinity procedure provides a general method for analysis of low abundance messenger RNAs.
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PMID:Identification and localization of mutations at the Lesch-Nyhan locus by ribonuclease A cleavage. 356 11

A simple and rapid spectrophotometric assay for the estimation of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity in human tissues is described. It is based on the increase in absorbance at 257.5 nm which occurs when the substrate guanine is converted to its 5'-mononucleotide, GMP. The assay has been developed to measure HGPRT activity in erythrocyte and lymphocyte lysates and in brain homogenates, and has been used in the screening of patients with hyperuricaemia and/or hyperuricosuria for HGPRT deficiency. It has also been used to determine the steady-state kinetic constants of a mutant form of the enzyme. The spectrophotometric assay is compared with the radioactive assay currently used to measure HGPRT activity.
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PMID:Human hypoxanthine-guanine phosphoribosyltransferase. Development of a spectrophotometric assay and its use in detection and characterization of mutant forms. 358 73

The CT brain scan of a 17-year-old patient with primary hyperuricaemia and mental retardation is presented. The examination demonstrates subcortical and cortical atrophy of the brain. The HGPRTase level was below normal. Clinical evidence of self-mutilation or tophi was not found. This patient's condition was interpreted as an incomplete Lesch-Nyhan syndrome.
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PMID:[Cranial computerized tomography in incomplete Lesch-Nyhan syndrome]. 358 89


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