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)

The ratio of the activities of catabolic enzymes such as 5'-nucleotidase and purine nucleoside phosphorylase to that of hypoxanthine-guanine phosphoribosyltransferase (HPRT) may be much higher in frozen or cultured chorionic villus cells than in cultured amniotic fluid cells, cultured fibroblasts, or red blood cells. Consequently, unless these catabolic activities are controlled the observed activity of HPRT may be greatly decreased, and a false diagnosis of Lesch-Nyhan syndrome may result. For a reliable diagnosis, the reaction products of HPRT must be protected from catabolism.
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PMID:A pitfall in the prenatal diagnosis of Lesch-Nyhan syndrome by chorionic villus sampling. 234 29

The Lesch-Nyhan (LN) syndrome is a genetically lethal human neurological disease that results from mutations that inactivate the hypoxanthine phosphoribosyltransferase (HPRT) gene. The elucidation of the complete DNA sequence of the human HPRT gene locus has enabled the construction of multiple oligonucleotide primer sets for the simultaneous in vitro amplification of all nine HPRT exons. The multiplex polymerase chain reaction provides a facile assay for the detection of HPRT exon deletions and the reaction products can be analyzed by direct automated fluorescent DNA sequencing to identify subtle alterations in the gene. Alterations have been identified in the HPRT genes from 15 independent LN cases, and 10 LN family studies were performed. The sequencing method uses solid supports and is sufficiently simple and sensitive to be a favored approach for LN diagnosis. LN heterozygotes can be diagnosed without reference to the affected male. In addition, these procedures will be useful for somatic mutagenesis studies.
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PMID:Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. 234 87

The spectrum of DNA sequence alterations in the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene of HPRTase-deficient T-lymphocytes isolated from the blood of healthy male donors was determined and compared with the spectrum found in patients suffering from genetic diseases (Lesch-Nyhan syndrome or gouty arthritis) associated with a mutation in the same gene. Most of the T-cell mutants still produced hprt mRNA which was converted into cDNA and used for DNA sequence analysis after amplification using the polymerase chain reaction (PCR). In 39% of the 31 analyzed T-cell mutants of normal donors 1 or 2 exons were completely or partially deleted from hprt mRNA, probably because of a mutation in a splice acceptor site. Among patients suffering from the Lesch-Nyhan syndrome or gouty arthritis, the class of splice mutations amounts only to 7%. These data suggest that carriers of splice mutations often do not show the characteristics of HPRTase deficiency associated with these genetic diseases, because correctly spliced hprt mRNA is still produced at a low level.
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PMID:Mutations affecting RNA splicing in man are detected more frequently in somatic than in germ cells. 238 50

Deficiencies of HPRT are usually associated with increased concentrations of PRPP and increased levels of APRT activity in erythrocytes. We report the case of a male with a partial deficiency of HPRT in whom these two parameters were normal. The clinical features of this patient were those associated with severe hyperuricaemia and gout. Studies of intact erythrocytes showed rates of incorporation of [14C]hypoxanthine and of [14C]adenine into purine nucleotides which were almost indistinguishable from normal. However, HPRT activity in erythrocyte lysates was only 9% of normal. In cell extracts of cultured lymphoblasts, the HPRT activity was 20% of control values and the APRT activity was normal. The PRPP concentration and the rate of de novo purine synthesis in cultured lymphoblasts were both intermediate between controls and lymphoblasts from patients with the Lesch-Nyhan syndrome.
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PMID:HPRT-deficiency associated with normal PRPP concentration and APRT activity. 243 88

Developmental retardation was a prominent clinical feature in six infants from three kindreds deficient in the enzyme purine nucleoside phosphorylase (PNP) and was present before development of T cell immunodeficiency. Guanosine triphosphate (GTP) depletion was noted in the erythrocytes of all surviving homozygotes and was of equivalent magnitude to that found in the Lesch-Nyhan syndrome (complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency). The similarity between the neurological complications in both disorders indicates that the two major clinical consequences of complete PNP deficiency have differing aetiologies: neurological effects resulting from deficiency of the PNP enzyme products, which are the substrates for HGPRT, leading to functional deficiency of this enzyme. immunodeficiency caused by accumulation of the PNP enzyme substrates, one of which, deoxyguanosine, is toxic to T cells. These studies show the need to consider PNP deficiency (suggested by the finding of hypouricaemia) in patients with neurological dysfunction, as well as in T cell immunodeficiency. They suggest an important role for GTP in normal central nervous system function.
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PMID:Central nervous system dysfunction and erythrocyte guanosine triphosphate depletion in purine nucleoside phosphorylase deficiency. 243 24

This paper reports the detection of five inherited disorders of purine and one of pyrimidine metabolism using intact red blood cells (RBCs) and compares the findings with those from RBC lysate activity. Two different phosphate levels (1 and 18 mmol L-1 Pi) were used to evaluate endogenous PP-ribose-P levels and their generation by PP-ribose-P synthetase. The importance of this dual approach is demonstrated by the following evidence: (a) Six out of eight patients with no detectable hypoxanthine-guanine phosphoribosyltransferase (HGPRT) RBC lysate activity had up to 25% of normal activity in their intact RBCs. Two Lesch-Nyhan patients showed no detectable activity in intact or lysed RBCs. (b) RBC lysates from two heterozygotes for adenosine deaminase (ADA) deficiency also showed no detectable activity, but up to 60% of normal activity using intact RBCs. (c) The existence of an aberrant enzyme in a kindred with a superactive PP-ribose-P synthetase was evident from the fact that intact RBCs failed to respond normally to phosphate activation, despite normal HGPRT and adenine phosphoribosyltransferase (APRT) RBC lysate activity. (d) Raised endogenous PP-ribose-P levels in intact RBCs were demonstrable only in purine nucleoside phosphorylase (PNP) and HGPRT deficiency; levels were normal in APRT deficiency and hereditary oroticaciduria (OPRT/ODC) deficiency. The results indicate that diagnosis from RBC lysate activity alone may be misleading. Intact RBC studies clearly provide a better indication of the functional capacity of the enzyme in vivo. They also show a closer correlation with the clinical phenotype and allow further insight into the associated biochemical abnormalities in some cases.
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PMID:Use of intact erythrocytes in the diagnosis of inherited purine and pyrimidine disorders. 244 57

We studied 5 boys, 2 to 10 years old, with marked or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase and Lesch-Nyhan syndrome with varying degrees of mental retardation, dysarthria, chorea, dystonia, spasticity, and ataxia. Four patients had marked reduction of homovanillic acid in the cerebrospinal fluid (CSF) and all showed low CSF 3-methoxy-4-hydroxy phenylethylene glycol, indicating reduced dopamine and norepinephrine turnover. Three patients showed high CSF 5-hydroxyindoleacetic acid, suggesting increased serotonin turnover. Some patients improved with carbidopa-levodopa, but others benefited from tetrabenazine, a monoamine-depleting agent. This study provides support for the theory of abnormal central monoamine metabolism in Lesch-Nyhan syndrome.
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PMID:Lesch-Nyhan syndrome: a study of motor behavior and cerebrospinal fluid neurotransmitters. 245 72

In mammals, X-chromosome dosage compensation is achieved by inactivating one X chromosome in female cells. To test the hypothesis that genes on the silent X chromosome reactivate as a consequence of ageing, we examined the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 41 women who are heterozygous for mutations at this locus, leading to severe deficiency of the enzyme (Lesch-Nyhan syndrome). We find that heterozygotes who are more than 10 yr old have an excess of HPRT+ skin fibroblast clones (59% rather than the 50% expected as a consequence of random X inactivation) but this excess does not increase with age. Further studies of eight of these heterozygotes show that the silent locus does not detectably reactivate spontaneously in culture, but only in response to treatment with 5-aza-2-deoxycytidine, a potent inhibitor of methylation. There is no age difference in the frequency of this reactivation as assayed by HATr clones, and a more sensitive autoradiographic assay shows only a twofold difference between young and old heterozygotes. Thus, age-related reactivation is not a feature of all X-linked loci, and may have species, tissue and locus-specific determinants.
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PMID:Effect of ageing on reactivation of the human X-linked HPRT locus. 291 84

Complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a devastating neurological disease, the Lesch-Nyhan syndrome. This disorder has been identified as a candidate for initial attempts at somatic cell gene therapy. We have previously reported the construction of a recombinant herpes simplex virus type 1 (HSV-1) vector containing human hprt cDNA sequences under the regulatory control of the viral thymidine kinase gene (tk) [Palella et al., Mol. Cell. Biol. 8 (1988) 457-460]. Infection of HPRT- cultured rat neuronal cells with these vectors resulted in transient expression of human hprt. In this paper, we report the expression of human hprt mRNA transcripts in the brains of mice infected in vivo with this vector by direct intracranial inoculation. Human hprt transcripts were distinguished from endogenous mouse transcripts by RNase A mapping using riboprobes transcribed from human hprt cDNA. These initial studies demonstrate the transfer and transcription of a human gene in brain cells by direct in vivo infection with recombinant HSV-1 vectors.
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PMID:Expression of human HPRT mRNA in brains of mice infected with a recombinant herpes simplex virus-1 vector. 255 79

The isoenzyme of hypoxanthine-guanine phosphoribosyltransferase (HPRT, E.C.2.4.2.8) functions in the metabolic salvage of purines. Partial HPRT deficiency is associated with gouty arthritis, while absence of activity results in Lesch-Nyhan (LN) syndrome. We characterized five unrelated patients with HPRT deficiency to understand the spectrum of molecular defects using Southern and Northern blot, polymerase chain amplification of HPRT mRNA and DNA sequencing, and oligonucleotide hybridization analysis of the HPRT gene. Southern blot analysis of DNA indicated that mutations leading to HPRT deficiency in our five patients were not the result of major chromosomal rearrangements or deletions. Sequencing analysis of the amplified DNA from three different patients with HPRT deficiency implied three unique molecular abnormalities: 1) one single-base substitution at codon 54 (from ATG to CTG) resulting in the replacement of methionine with leucine in an LN patient, 2) two single-base substitutions at codon 179 (from GTT to GGT) and at codon 180 (from GGA to AGA) resulting in the replacement of valine with glycine and glycine with arginine in a gouty patient, and 3) 51 nucleotide deletion between nucleotides 747 and 797 resulting in the formation of shorter sized HPRT mRNA and putative two amino-acid deleted HPRT protein in another gouty patient. These results are the direct molecular evidence of genetic heterogeneity in mutant HPRT.
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PMID:Molecular analysis of hypoxanthine-guanine phosphoribosyltransferase mutations in five unrelated Japanese patients. 257 41


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