Disease relevance of HPRT1

• In this research we demonstrate a model for Lesch-Nyhan disease by mutating the HPRT1 gene in human ES cells using homologous recombination [1].
• Rare forms of hyperuricemia and gout are due to mutations of X-linked genes (HPRT1 and PRPS1) [2].
• Lesch-Nyhan disease is caused by a mutation in the HPRT1 gene that triggers an overproduction of uric acid, causing gout-like symptoms and urinary stones, in addition to neurological disorders [1].
• Effect of exogenous MSH6 and POLD1 expression on the mutation rate of the HPRT locus in a human colon cancer cell line with mutator phenotype, DLD-1 [3].
• In this study, expression stability of six supposed control genes was evaluated in 64 samples of primary neuroblastoma and HPRT1 and SDHA mRNA levels were shown to exhibit the least expression variability among the samples [4].

Psychiatry related information on HPRT1

• The inherited disease Lesch-Nyhan syndrome, which is caused by a deficiency of the enzyme hypoxanthine phosphoribosyltransferase (HPRT), is characterized by behavioural alterations, including self-injurious behaviour and mental retardation [5].
• Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior [6].
• HGPRT in the Gilles de la Tourette syndrome [7].
• HPRT-deficient mice generated using mouse embryonic stem cells exhibit none of the behavioral symptoms associated with the Lesch-Nyhan syndrome [8].
• To gain insight into V(D)J recombinase-mediated events during human development, we investigated 265 coding junctions associated with cRSS sites at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in peripheral T cells from 111 children during the late stages of fetal development through early adolescence [9].

High impact information on HPRT1

• Mutant mice express a form of the HPRT protein that contains a long polyglutamine repeat [10].
• A rationalization of the effects on stability and activity of naturally occurring single amino acid mutations of HGPRTase is presented, including a discussion of several mutations at the active site that lead to Lesch-Nyhan syndrome [11].
• The location of active site residues also provides evidence for a possible mechanism for general base-assisted HGPRTase catalysis [11].
• To determine whether Langerhans' histiocytosis is a polyclonal reactive disease or a clonal disorder, we used X-linked polymorphic DNA probes (HUMARA, PGK, M27 beta[DXS255], and HPRT) to assess clonality in lesional tissues and control leukocytes from 10 female patients with various forms of the disease [12].
• Although HPRT-deficient mice have been generated using the embryonic stem cell system, no spontaneous behavioural abnormalities had been reported [5].

Chemical compound and disease context of HPRT1

• Hypoxanthine phosphoribosyltransferase (HPRT1) is a key enzyme in the purine salvage pathway, and mutations in HPRT1 cause Lesch-Nyhan disease [13].
• This sequence has previously been shown to be a likely catalytic domain in human HPRT and Escherichia coli glutamine phosphoribosyltransferase [14].
• HPRT Ann Arbor is a variant of hypoxanthine (guanine) phosphoribosyl-transferase (HPRT: EC 2.4.2.8), which was identified in wo brothers with hyperuricemia and nephrolithiasis [15].
• Hypoxanthine-guanine phosphoribosyltransferase mutant glioma cells: diminished monamine oxidase activity [16].
• 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 [17].

Biological context of HPRT1

• Lastly, a sequence highly homologous to HPRT1 exon 8 was found on chromosome 10 [18].
• This gene with unknown function is almost completely homologous to HPRT1 in exon structure (except for a 21 bp (seven amino acid) insertion in exon 1) and 68% homologous in amino acid sequence [18].
• Pseudogenes of the human HPRT1 gene [18].
• In this study, we have identified a novel mechanism of mutation involving translocation between the HPRT1 loci and other loci on the X chromosome [19].
• Inherited mutations in the human HPRT1 gene result in three different phenotypes: Lesch-Nyhan syndrome (LNS or LND), LND variants, and HPRT-related hyperuricemia (HRH) [20].

Anatomical context of HPRT1

• However, the mRNA level of GAPDH relative to HPRT1 in rat hepatocytes was markedly increased by Rif [21].
• In addition, PMCA4 expression shows little variation across eight drug-treated cell lines and was found to be superior to GAPDH and HPRT1, commonly used reference genes [22].
• The HPRT gene on the X chromosome is transcriptionally active in male human fibroblasts [23].
• We report here two in vivo somatic HPRT1 mutations in human kidney tubular epithelial cells that disrupt HPRT1 intron 1 splicing and lead to the inclusion of intron 1 sequence [24].
• The mutation G508A in the HPRT1 gene has been repeatedly found among peripheral T lymphocytes by clonal expansion under selective conditions [25].

Associations of HPRT1 with chemical compounds

• By using selection media, we show that HPRT1 activity is abolished in the mutant cells, and the HPRT1-cells show a higher rate of uric acid accumulation than the wild-type cells [1].
• ACTB and HPRT1 are suitable internal controls for evaluating mRNA expression levels in primary cultures of human and rat hepatocytes after Rif, Dex, or Ome exposure [21].
• We identified the identical large genomic deletion in the hypoxanthine phosphoribosyltransferase (HPRT1) gene in two Japanese patients with Lesch-Nyhan (LN) syndrome [26].
• DNA sequences of the X-chromosome-linked hypoxanthine phosphoribosyltransferase (HPRT) and glucose 6-phosphate dehydrogenase (G6PD) genes have revealed the presence of clusters of CpG dinucleotides, raising the possibility that such clusters are involved in the control of expression of these genes, which are expressed in all tissues [27].
• Aberrant hypoxanthine phosphoribosyltransferase (HUGO-approved gene symbol HPRT1; MIM# 308000) mRNA splicing, promoted by splice site mutation or loss, is a common mechanism for loss of the purine salvage enzyme HPRT1 from human cells [24].

Regulatory relationships of HPRT1

• Mutagenicity of IQ and MeIQx at the hypoxanthine-guanine phosphoribosyltransferase locus was also detectable only in ANP-25 cells but not in A2R-5 or the cell line expressing CYP1A2 plus NAT1 [28].
• Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase [29].
• We evaluated the role of polymerase eta in translesion synthesis past platinum adducts by determining cytotoxicity and induced mutation frequencies at the hypoxanthine guanine phosphoribosyltransferase (HPRT) locus in diploid human fibroblasts [30].
• The mutant frequency at the hypoxanthine-guanine phosphoribosyltransferase locus in peripheral blood lymphocytes was measured for 254 atomic bomb survivors (171 exposed and 83 control survivors) by a colony assay using recombinant human interleukin-2 [31].
• In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity [32].

Other interactions of HPRT1

• Therefore, we examined the effect of exogenous wild-type MSH6 and POLD1 expression on the spontaneous mutation rate at the HPRT locus in DLD-1 cells [3].
• POLB exhibits a high frequency of splice variants (40-60%), whereas the frequency of HPRT splice variants is considerably lower (approximately 1%) [33].
• Unknown sequence compared through BLAST analysis of human genome (NCBI; http://www.ncbi.nlm.nih.gov/BLAST/) showed that at least 0.5 to 0.6-Mb telomeric to HPRT1 on chromosome Xq where located near LOC340581 [19].
• The use of 3' rapid amplification of cDNA ends polymerase chain reaction (3'RACE-PCR) for HRT-25 revealed part of intron 3 and an unknown sequence which have not identified the HPRT1 gene starting at the 3' end of exon 3 [19].
• These results strongly suggest that there is coordinate reactivation of GLA and HPRT [34].

Analytical, diagnostic and therapeutic context of HPRT1

• This origin was mapped using a quantitative PCR assay to evaluate the relative abundance of HPRT markers in short nascent DNA strands isolated from asynchronous cultures of male fibroblasts [23].
• Reliable transcript quantification by real-time reverse transcriptase-polymerase chain reaction in primary neuroblastoma using normalization to averaged expression levels of the control genes HPRT1 and SDHA [4].
• Comparison with transcript levels determined by oligonucleotide-array expression analysis revealed that target gene mRNA quantification became most consistent after normalization to averaged expression levels of HPRT1 and SDHA [4].
• Isoelectric focusing showed that the HPRT expressed in these clones is human [35].
• Southern blot analysis of genomic DNA isolated from lymphoblasts derived from G.S. and D.B. revealed that both have this additional Hpa I site, indicating that the similarly altered protein sequence is due to the identical transition in the HPRT gene [36].

References