Alternative titles; symbols
HGNC Approved Gene Symbol: HPRT1
SNOMEDCT: 10406007, 124275001, 238007004; ICD10CM: E79.1;
Cytogenetic location: Xq26.2-q26.3 Genomic coordinates (GRCh38): X:134,460,165-134,500,668 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26.2-q26.3 | Hyperuricemia, HRPT-related | 300323 | X-linked recessive | 3 |
| Lesch-Nyhan syndrome | 300322 | X-linked recessive | 3 |
HPRT1 has a central role in the generation of purine nucleotides through the purine salvage pathway. HPRT1 encodes hypoxanthine phosphoribosyltransferase (EC 2.4.2.8), which catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate (summary by Keebaugh et al., 2007).
Jolly et al. (1982) isolated a genomic clone partially encoding human HPRT. Jolly et al. (1983) cloned a full-length 1.6 kb cDNA of a human mRNA coding for HPRT into an SV40-based expression vector and determined its full nucleotide sequence.
Patel et al. (1986) reported that the HPRT gene is about 44 kb long and contains 9 exons; see also Kim et al. (1986) and Melton et al. (1984).
X-linkage was first suggested by Hoefnagel et al. (1965) and was supported by a rapidly accumulated series of families with deficiency of HPRT. Studies using human-mouse somatic cell hybrids indicated, by reasoning similar to that used for locating the thymidine kinase locus to chromosome 17 (188300), that the HPRT locus is on the X chromosome (Nabholz et al., 1969).
Studying X-autosome translocations in somatic cell hybrids, Pai et al. (1980) showed that a breakpoint at the junction of Xq27-q28 separates HPRT from G6PD (305900). G6PD is distally situated at Xq28. They localized HPRT to the segment between Xq26 and Xq27.
Gross (2017) mapped the HPRT1 gene to chromosome Xq26.2 based on an alignment of the HPRT1 sequence (GenBank AY780550) with the genomic sequence (GRCh38).
Three HPRT pseudogenes, located on chromosomes 3, 5 and 11, have been identified (Stout and Caskey, 1984). Dobrovic et al. (1987) identified a RFLP for the HPRT pseudogene on chromosome 3 (HPRTP1).
For more detailed information on HPRT1 mapping studies, see HISTORY.
To define genomic elements required for HPRT1 expression in HAP1 human myelogenous leukemia cells, Gasperini et al. (2017) induced large CRISPR/Cas9-based deletions in a 206-kb region surrounding the HPRT1 gene. All 9 exons were required for HPRT1 expression and function, as measured by sensitivity to the purine analog 6-thioguanine. No distal 5-prime regulatory element was detected, and only a narrow window of noncoding sequence immediately upstream of the transcriptional start site and 5-prime UTR was required for HPRT1 expression.
Gibbs and Caskey (1987) used the ribonuclease A cleavage procedure, with a polyuridylic acid-paper affinity chromatography step, to identify the mutation lesions in the HPRT mRNA of patients with Lesch-Nyhan syndrome (LNS; 300322). Of 14 patients chosen because no HPRT Southern or Northern blotting pattern changes had been found, 5 were shown to have a distinctive ribonuclease A cleavage pattern in messenger RNA. This method makes it possible to assay for point mutation. The method had been used to characterize beta-globin mutations in genomic DNA (Myers et al., 1985) and KRAS variants in RNA from tumor cell lines. The ribonuclease A cleavage assays are based on the fact that some single-base mismatch sites in RNA hybrids with RNA or DNA will be cleaved by RNase A. Cleavage occurs because of the single-stranded status of a region within the hybrid. Since Southern and Northern blots show rearrangements in about 15% of cases, combination of these methods with the ribonuclease A cleavage method permits identification of abnormality in about 50% of cases. Simpson et al. (1988) described a method of PCR (polymerase chain reaction) for cloning and sequencing specific human HPRT cDNAs for mutation analysis. Yang et al. (1984) found that the mutations in 7 Lesch-Nyhan patients were different. They demonstrated how it is possible to trace the origin of new mutations by molecular genetic methods. Gibbs et al. (1989) used automated direct DNA sequence analysis of amplified HPRT cDNA to detect and characterize nucleotide alterations in 15 independent mutations causing HPRT deficiency. Davidson et al. (1989) used the PCR method to identify the mutations in HPRT mRNA from B-lymphoblasts derived from 10 deficient individuals. Six contained single point mutations, 3 contained deletions, and 1 contained a single nucleotide insertion. Several of these mutations mapped near previously identified HPRT variants and are located in evolutionarily conserved regions of the molecule. Edwards et al. (1990) reported the complete sequence of 57 kb of DNA at the HPRT locus. Ogasawara et al. (1989) studied a 9-year-old girl with typical biochemical and behavioral characteristics of the Lesch-Nyhan syndrome. Cytogenetic and carrier studies showed structurally normal chromosomes in the patient and her parents and demonstrated that the mutation arose through a de novo gametic event. DNA studies showed a microdeletion that occurred in a maternal gamete and involved the entire HPRT gene. However, in addition to this, by study of somatic cell hybrids generated to separate maternal and paternal X chromosomes, Ogasawara et al. (1989) showed that there was a nonrandom inactivation of the cytogenetically normal paternal X chromosome. Specifically, 2 other X-linked enzymes, phosphoglycerate kinase and G6PD, were expressed only in somatic cell hybrid cells that contained the maternal X chromosome. Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation showed differences between the DNA of the father and that of the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient.
In Southern blot patterns, Sinnett et al. (1988) found no evidence of major structural alterations in the HPRT gene in 3 French Canadian families with LNS. Northern analysis using HPRT cDNA as a probe showed no hybridizing RNA in an affected member of 1 family, whereas normal-sized mRNA was expressed at a very low level in the second family and at a level comparable to the normal in the third. These data and other information presented here indicate the heterogeneity of LNS resulting from point mutations or small DNA deletions or rearrangements, which may affect transcription, stability, or integrity of the HPRT message. Seegmiller (1989) gave a useful overview of the substantial contributions of the Lesch-Nyhan syndrome to the understanding of purine metabolism, thus illustrating the garrodian principle of the usefulness of rare genetic diseases to the understanding of biology and medicine.
In reporting lesions in the HPRT gene, the initiation methionine codon has been counted as position 1 in some reports (e.g., Wilson et al., 1983; Fujimori et al., 1988), whereas the codon for the first amino acid of the mature protein has been used in others (e.g., Gibbs et al., 1989). In the listing that follows, the initiation methionine codon is counted as number 1 throughout.
See Rossiter et al. (1991) for a tabulation of HPRT mutations causing Lesch-Nyhan syndrome. A notable feature of the list is the great variety of mutations that can cause the Lesch-Nyhan syndrome and the rarity of 'repeat' mutations: HPRT London (308000.0010), a cause of precocious gout, occurred in 2 unrelated persons; only the his203-to-asp mutation (308000.0019) had been found in 2 unrelated LNS patients.
Sculley et al. (1992) reviewed the mutations involving the coding region of HPRT. These included 32 that predictably cause changes in the size of the translated protein and 38 that represent mutations causing a single amino acid substitution. They commented that in the absence of precise information on the 3-dimensional structure of the HPRT protein, it remains difficult to determine any consistent correlation between structure and function of the enzyme. Boyd et al. (1993) used heteroduplex detection by hydrolink gel electrophoresis in screening for mutations in families with Lesch-Nyhan syndrome.
In their Figure 3, Renwick et al. (1995) provided a summary map of the HPRT mutations identified as causing disease in humans. Insertions and deletions, as well as point mutations, were indicated. They stated that 17 microdeletions, most of them less than 20 bp, had been identified. Gross alterations involving the HPRT gene found by Southern analysis using cDNA probes included 3 total gene deletions, 3 partial gene deletions involving the 3-prime portion, 2 duplications, and a possible insertion. These gross DNA alterations accounted for only 12% of reported Lesch-Nyhan cases. They reported another case, that of a 5-kb deletion that had its end points in the first and third introns and was responsible for Lesch-Nyhan syndrome.
Colgin et al. (2002) studied the HPRT gene to investigate the spectrum and frequency of somatic mutations in kidney tubular epithelial cells. Studies were done in primary tubular epithelial cell clones grown directly from human kidney tissue. The authors found that mutant tubular epithelial cells, recovered by growth in the purine analog 6-thioguanine (TG), were surprisingly frequent. Mutant frequency increased approximately 1% per year of donor age and was 10-fold or more higher in kidney than in peripheral blood T lymphocytes of normal, age-matched donors. Most TG-resistant kidney tubular epithelial cells from single donors contained different HPRT mutations. A high proportion of the mutations represented unreported HPRT base substitutions, 1-bp deletions, and multiple mutations. This spectrum of somatic mutations differed from HPRT mutations found in human peripheral blood T lymphocytes and from germline HPRT mutations identified in Lesch-Nyhan syndrome or hyperuricemia patients. The results indicated that DNA damage and mutagenesis may have unusual features in kidney tubular epithelium and that somatic mutation may play a more important role in human kidney disease than previously appreciated.
Ceballos-Picot et al. (2009) demonstrated that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient sublines derived from the hybrid MN9D cell line, derived from somatic fusion of embryonic mouse primary midbrain dopaminergic neurons and a mouse neuroblastoma cell line. There were consistent increases in mRNAs for engrailed-1 (EN1; 131290) and -2 (EN2; 131310), transcription factors known to play a role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels. The functional relevance of the abnormal developmental molecular signature of the HPRT-deficient MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. These abnormalities were also seen in HPRT-deficient sublines from the SK-N-BE(2)-M17 human neuroblastoma line, and overexpression of engrailed was documented in primary fibroblasts from patients with Lesch-Nyhan disease. Ceballos-Picot et al. (2009) concluded that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms.
In a molecular analysis of 85 French and Italian patients with HPRT mutations, including 54 with LNS, 19 with the LNS neurologic variant, and 12 with HRH, Madeo et al. (2019) found that complex rearrangements, nonsense mutations, wide deletions, and splicing mutations were almost always associated with neurologic and behavioral manifestations, corresponding to an LNS or, less frequently, LNS with neurologic phenotype, while missense mutations were found in all 3 subgroups, but more frequently in the attenuated variants. However, intrafamilial phenotypic variability was also found.
Using comparative mapping and sequencing, in conjunction with database analysis, Keebaugh et al. (2007) showed that the HPRT gene family expanded as a result of ancient vertebrate-specific duplications and is composed of 3 groups: HPRT1, PRTFDC1 (610751) and Hprt1l, which is found only in fish. These 3 gene groups have distinct rates of evolution and potentially divergent function. Keebaugh et al. (2007) noted that HPRT1 is an X-linked gene in placental mammals and marsupials, whereas in other vertebrates it is located on an autosome.
Hooper et al. (1987) and Kuehn et al. (1987) independently reported success in generating HPRT-deficient male mice by injecting into normal embryos pluripotential stem cells which had first been selected as HPRT-negative in tissue culture. They found that the germline was colonized by these cultured cells with resulting germline chimerism and production of female offspring heterozygous for HPRT deficiency. In this way it was possible to derive strains of mutant mice having the same biochemical defect as Lesch-Nyhan patients. The availability of such mice should permit study of the molecular basis of the phenotype in this disorder. HPRT is an ideal gene for these studies because it is expressed by all cells and only 1 copy needs to be eliminated in XY cell lines to produce enzyme deficiency; because the gene presents a reasonable target size (34 kb) and cloned probes enable the sites of mutation to be mapped; and particularly because a powerful technique is available for selecting HPRT-negative cells. Since these cells, unlike HPRT-positive cells, are unable to salvage free purine bases, they are not killed when toxic purine analogs such as 6-thioguanine and 8-azoguanine are added to the culture medium. The method used by these workers depended on embryonic stem (ES) cells that can still enter the germline after genetic manipulation in culture. Doetschman et al. (1987) used homologous recombination between the HPRT gene and exogenous DNA for targeted correction of the HPRT locus in the ES cell line that had previously been isolated and used to produce an HPRT-deficient mouse. Koller et al. (1989) injected the 'corrected' embryonic stem cells into blastocysts which were introduced into pseudopregnant female mice to complete their development. Nine chimeric pups (6 males, 3 females) were obtained. Two of the males transmitted the embryonic stem cell genome containing the alteration in the HPRT gene to their offspring at high frequencies. Using a mouse model of HPRT deficiency, Monk et al. (1987, 1990) showed that sexing and diagnosis of the deficiency could be performed in preimplantation embryos by biochemical microassay. The diagnoses were sufficiently rapid that freezing of the embryos before transfer was not necessary. Sexing was possible because both X chromosomes are active in female morulae and the blastomeres sampled from female preimplantation embryos have twice as much X-encoded HPRT activity as do blastomeres from male embryos. Wu and Melton (1993) examined the question of why HPRT-deficient mice generated using the embryonic stem cell system show no spontaneous behavioral abnormalities characteristic of Lesch-Nyhan syndrome. They suspected that mice are more tolerant of HPRT deficiency because they are more reliant on adenine phosphoribosyltransferase (APRT; 102600) than HPRT for their purine salvage. Pursuing this idea, they administered an APRT inhibitor to HPRT-deficient mice and induced persistent self-injurious behavior.
Engle et al. (1996) bred HPRT/APRT doubly deficient mice in an attempt to induce behavioral manifestations characteristic of Lesch-Nyhan syndrome in humans. They noted that HPRT-deficient mice showed no behavioral abnormalities. The APRT/HPRT-deficient mice who were void of any purine salvage pathways showed no novel behavioral phenotype.
Rosenbloom et al. (1967) and Migeon et al. (1968) demonstrated 2 populations of fibroblasts, as regards the relevant enzyme activity, in heterozygous females, thus providing support both for X-linkage and for the Lyon hypothesis. Silvers et al. (1972) demonstrated mosaicism by study of hair roots in women heterozygous for Lesch-Nyhan syndrome (LNS; 300322), which is due to complete deficiency of HPRT. Francke et al. (1976) studied the frequency of new mutations among affected males. Lesch-Nyhan syndrome is particularly favorable for this purpose because no affected males reproduce, the diagnosis is unequivocal, cases come readily to attention, and heterozygosity can be demonstrated in females by the existence of 2 populations of cultured fibroblasts. There were few new mutations, contrary to the expected one-third. On the other hand, about one-half of heterozygous females were new mutations, as is predicted by theory. The finding may indicate a higher frequency of mutation in males than in females. Another possibility is the role of somatic and half-chromatid mutations (Gartler and Francke, 1975). New mutation cases of heterozygous females had elevated parental age. Vogel (1977) reviewed the evidence concerning hemophilia and Lesch-Nyhan syndrome leading to the conclusion that the mutation rate is higher in males than in females. Evidence that the mutation rate for Lesch-Nyhan disease may be higher in males than in females was reviewed by Francke et al. (1976) and criticized by Morton and Lalouel (1977). Francke et al. (1977) answered the criticism. Strauss et al. (1980) showed that females heterozygous for the Lesch-Nyhan mutation have 2 populations of peripheral blood lymphocytes with regard to sensitivity to 6-thioguanine inhibition of tritiated thymidine incorporation following phytohemagglutinin stimulation.
Henderson et al. (1969) concluded that the locus for HPRT is closely linked to the Xg (314700) locus; Greene et al. (1970) concluded, however, that the HPRT and Xg loci 'are sufficient distance from each other on the human X chromosome that linkage cannot be detected.' Nyhan et al. (1970) observed a sibship in which both HPRT deficiency and G6PD deficiency (300908) were segregating and found 2 recombinants out of 4. Nyhan et al. (1970) also found that heterozygotes had normal levels of HPRT in red cells. They interpreted this as indicating a selective advantage of G6PD-normal over G6PD-deficient cells. (In adrenoleukodystrophy (300100), it is the mutant cell that enjoys the selective advantage.)
In mouse-man hybrid cells, when the mouse parent cell is of the type called RAG which is resistant to 8-azaguanine because of a deficiency of HPRT, the human form of HPRT is required in order for the hybrid cells to survive in HAT selective medium. In over 100 clones of human-RAG hybrid cells maintained in HAT, Ruddle (1971) saw without exception persistence of human G6PD activity. This strongly indicated either close linkage of the HPRT and G6PD loci or a very low incidence of X-chromosome breakage and rearrangement. Emmerson et al. (1974) excluded close linkage of the HPRT and the deutan colorblindness (303800) loci. That the HPRT locus is X-linked in the mouse also was indicated by Epstein (1972) finding that the activity of the enzyme at the 2-cell stage in the XO product is half that in the XX. No difference is observed in late morula and blastocyst stage. G6PD and HPRT are linked in the Chinese hamster (Rosenstraus and Chasin, 1975) and presumably are on the X chromosome as in man.
By study of cell hybrids, Shows et al. (1976) found that HPRT and G6PD are closely linked in the muntjac deer. From study of radiation-induced segregants (irradiated human cells 'rescued' by fusion with hamster cells), Goss and Harris (1977) showed that the order of the 4 loci is PGK: alpha-GAL: HPRT: G6PD and that the 3 intervals between these 4 loci are, in relative terms, 0.33, 0.30, and 0.23. Alpha-GAL, HPRT, PGK (172270), and G6PD were found to be X-linked in rabbit hybrid cell studies (Cianfriglia et al., 1979; Echard and Gillois, 1979). By comparable methods, Hors-Cayla et al. (1979) found them to be X-linked also in cattle. According to cell hybridization studies, HPRT, G6PD and PGK, are also X-linked in the pig (Gellin et al., 1979) and in sheep (Saidi et al., 1979). Francke and Taggart (1979) assigned HPRT and alpha-GAL to the X chromosome in the Chinese hamster by study of mouse-Chinese hamster hybrid cells. It is remarkable that although the HPRT and G6PD loci appear from physical mapping to be closely situated, family studies indicate considerable recombination (Francke et al., 1974). Fenwick (1980) assigned the HPRT, G6PD, and PGK loci to the short arm of the Chinese hamster X chromosome.
Fujimori et al. (1988) showed that the change in HPRT(Ann Arbor) is a single nucleotide change (T-to-G) at nucleotide position 396. This transversion predicts an amino acid substitution from isoleucine (ATT) to methionine (ATG) in codon 132, which is located within the putative PRPP-binding site of HPRT. HPRT(Ann Arbor) was identified in 2 brothers with hyperuricemia and nephrolithiasis (HRH; 300323).
In a male with gout and partial HPRT deficiency (HRH; 300323), Davidson et al. (1989) found an A-to-T change at nucleotide 239, changing aspartic acid-80 to valine.
Davidson et al. (1989) identified an A-to-G transition at nucleotide 602, leading to a substitution of glycine for aspartic acid as amino acid 201 in a variant referred to as HPRT(Ashville). The man with this mutant had severe precocious gout and uric acid nephrolithiasis, due to overproduction of uric acid, and partial HPRT deficiency (HRH; 300323).
In a patient with Lesch-Nyhan syndrome (LNS; 300322), Davidson et al. (1989) demonstrated insertion of 1 nucleotide, a T, as either no. 56, 57, or 58. This led to a change of CCTTGA to CCTTTGA and termination of translation at asp20.
In a patient with LNS (300322), Davidson et al. (1989) found deletion of nucleotides 532-609 (all of exon 8) causing loss of phe178 to asn203. A change in reading frames results in a stop codon 15 nucleotides downstream from the junction between exons 7 and 9.
In a patient with LNS (300322), Davidson et al. (1989) found that a change of nucleotide 122 from T to C caused substitution of proline for leu41.
In a patient with LNS (300322), Davidson et al. (1989) found an HPRT protein abnormally long by 24 amino acids, resulting from change in nucleotides 643 to 663 which code for the last 4 amino acids and the stop codon. This mutation was also reported by Gibbs et al. (1990) in cell line RJK894. (RJK = Robert J. Kleberg, a major benefactor of the Institute of Medical Genetics at Baylor College of Medicine.)
In a patient with LNS (300322), Davidson et al. (1988) found a C-to-A change that converted phenylalanine-74 to leucine. (The cell line is also known as RJK896 (Gibbs et al., 1990).) This mutation is the same as that in HPRT Perth, which was identified as an independent mutation by Sculley et al. (1991) in a patient with Lesch-Nyhan syndrome in Australia.
HPRT(Kinston) has a G-to-A change resulting in substitution of asparagine for aspartic acid as amino acid 194 (Wilson and Kelley, 1983). Gibbs et al. (1990) described an asp193-to-asn substitution in cell line RJK2188 from a patient with LNS (300322). This is the same as HPRT Kinston; Gibbs et al. (1990) used the numbering system not counting the initial methionine, whereas Wilson and Kelley (1983) did use it.
Wilson et al. (1983) found substitution of leucine for serine at amino acid 109 in HPRT(London). Davidson et al. (1988) showed that HPRT(London), observed in 2 apparently unrelated individuals and resulting in partial HPRT deficiency and gout (HRH; 300323), is the result of a mutation that causes substitution of leucine for serine at amino acid 110. The DNA change is a C-to-T transition at bp 329. This transition creates an HpaI site in exon 4 of the HPRT gene. This is explicable by change from UCA to UUA in codon 109.
In a case of LNS (300322), Davidson et al. (1989) showed that the mutation is a deletion of nucleotides 535-537 resulting in loss of valine 179.
In a patient with Lesch-Nyhan syndrome (300322), Davidson et al. (1988) and Gibbs et al. (1989) found a T-to-A change resulting in substitution of aspartic acid for valine-130.
In a patient with partial HPRT deficiency and gout (HRH; 300323), Davidson et al. (1989) found a change of nucleotide 481 from G to T resulting in substitution of alanine-161 by serine. (The cell line is RJK949 of Gibbs et al. (1989).)
By a combination of denaturing gradient gel electrophoresis and in vitro DNA amplification, Cariello et al. (1988) localized a DNA mutation to a given 100-bp region of the human genome and rapidly sequenced the DNA without cloning. The mutation studied by Cariello et al. (1988), HPRT(Munich), came from a patient with gout (HRH; 300323); it was found to represent a single basepair substitution, a C-to-A transversion at basepair 312. (This was reported as 397 by Cariello et al. (1988) because of a different system of numbering nucleotides.) Wilson and Kelley (1984) defined it as a ser104-to-arg bp substitution by studies of protein sequence, and Palella (1990) later determined the nucleotide change as C-to-T.
In a case of LNS (300322), Davidson et al. (1989) showed that a T-to-G change in nucleotide 595 produced a substitution of phe199 by valine. (This is the same as cell line RJK950, studied by Gibbs et al. (1989).)
In a case of LNS (300322), Davidson et al. (1989) showed that a G-to-A change in nucleotide 209 resulted in substitution of gly70 by glutamic acid.
In the mutant HPRT(Yale), discovered in a subject with LNS (300322), Wilson et al. (1986) found normal mRNA in protein concentrations, no residual catalytic activity, and cathodal migration upon PAGE. By cloning and sequencing HPRT(Yale) cDNA, Fujimori et al. (1989) found a single nucleotide substitution: G-to-C at nucleotide position 211. This transversion predicted substitution of arginine for glycine at amino acid position 71, explaining the cathodal migration of HPRT(Yale). Inclusion of the bulky arginine side chain in place of glycine probably disrupts protein folding.
Gibbs et al. (1990) described this mutation in cell line RJK1930 from a patient with LNS (300322).
Gibbs et al. (1989) described this mutation in cell line RJK1874 from a patient with LNS (300322). Gibbs et al. (1990) found the same mutation in an unrelated patient with LNS (RJK2019).
Gibbs et al. (1990) described this mutation in cell line RJK2163 from a patient with LNS (300322).
Gibbs et al. (1990) described this mutation in cell line RJK2185 from a patient with LNS (300322).
In cell line RJK1747 from a patient with LNS (300322), Gibbs et al. (1990) found deletion of 2 nucleotides (GT) causing a frameshift.
In cell line RJK1939 from a patient with LNS (300322), Gibbs et al. (1990) found deletion of 1 nucleotide (TTA-to-TA) resulting in a frameshift.
In cell line RJK2019 from a patient with LNS (300322), Gibbs et al. (1990) found deletion of 1 nucleotide (TTG-to-TG) resulting in a frameshift.
In cell line RJK2108 from a patient with LNS (300322), Gibbs et al. (1990) found deletion of 40 nucleotides resulting in a frameshift.
In cell line RJK888 from a patient with LNS (300322), Gibbs et al. (1990) found a G-to-A change of the fifth nucleotide in intron 8 causing a defect in splicing because of the change in the donor site.
In cell line RJK906 from a patient with LNS (300322), Gibbs et al. (1990) found an ATAG-to-TTTG change in the last 4 nucleotides of intron 8. Interference with processing resulted from mutation in the acceptor splice site.
In cell line RJK1934 from a patient with LNS (300322), Gibbs et al. (1990) found a GTAAGT-to-GTAAAT change at the beginning of intron 7. Interference with processing resulted from mutation in the donor splice site. See 308000.0029 for the corresponding mutation in intron 8.
In cell line RJK1760 from a patient (CB) with LNS (300322), Gibbs et al. (1990) found an AG-to-TG change in the last 2 nucleotides of intron 1. Interference with processing resulted from mutation in the acceptor splice site.
Davidson et al. (1989) referred to their observations concerning this mutation. The substitution predicts loss in beta-turn structure and change in hydrophilicity which may be essential to normal enzymatic function since this and the Evansville and Milwaukee mutations have greatly diminished or undetectable enzyme activity. (Davidson (1990) identified the mutation as pro176leu rather than pro174leu as published.)
In a patient with gout (HRH; 300323), Wilson et al. (1983) found substitution of glycine (GGA) for arginine-51 (CGA) in the HPRT gene.
In a Japanese patient with Lesch-Nyhan syndrome (300322), Fujimori et al. (1990) identified a change of codon 51 from CGA(arg) to TGA(stop). The same codon, although a different nucleotide, is involved in HPRT(Toronto). HPRT(Toronto) is associated with incomplete deficiency leading to gout and not the Lesch-Nyhan syndrome.
Skopek et al. (1990) used DNA from peripheral blood T-lymphocytes to demonstrate a single base substitution (T-to-C transition) at position 170 (exon 3). The predicted amino acid change was a substitution of threonine for methionine-56. The probands were 2 male children in a French Canadian family. Both had developmental delay, mainly motor in nature, and were confined to a wheelchair by age 5. Neither had aggressive behavior or self-mutilation (see 300322). HPRT activities were 18% and 10% of parental values for the older and younger boy, respectively.
In patient GB (RJK1210) with LNS (300322), Gibbs et al. (1989) found a TGC-to-AGC change at nucleotide 428 in exon 6, causing a met143-to-lys substitution.
In patient JC (RJK 974) with LNS (300322), Gibbs et al. (1989) found a CGA-to-TGA change in codon 170. In a family containing at least 3 males with Lesch-Nyhan syndrome, Marcus et al. (1992) identified a nonsense mutation at the CpG site in the codon for arginine-169, by genomic PCR and DNA sequencing in cultured fibroblasts. The recurrence of mutation at this site in several unrelated Lesch-Nyhan families suggested deamination of 5-methylcytosine as a mechanism for mutagenesis. The level of HPRT mRNA in the fibroblasts of the patients was similar to that in healthy controls, whereas HPRT enzyme activity was not detectable. A noncarrier phenotype was found in hair follicle analyses and fibroblast selection studies in 8-azaguanine and 6-thioguanine medium in 3 of the obligatory female heterozygotes, whereas X-inactivation mosaicism was demonstrated in 1 heterozygote. Marcus et al. (1992) raised the possibility that the HPRT mutation was associated with an undefined X-linked lethal mutation leading to the nonrandom X-inactivation. The observation is of practical relevance for carrier detection in other Lesch-Nyhan families. The mutation called ARG169TER by Marcus et al. (1992) is the same as that numbered arg170-to-ter by Gibbs et al. (1989). Tarle et al. (1991) found the same mutation. Marcus et al. (1992) quoted Gibbs as having found 3 additional unrelated patients with the same mutation which may account for about 15% of the base substitution mutations identified so far.
De Gregorio et al. (2000) reported an Argentinian family in which a 22-year-old male and his 8-year-old sister had clinically identical classic features of LNS. The mother and an older daughter were carriers and had normal phenotypes. The affected sister was karyotypically normal and heterozygous for the R169X mutation. She inherited the HPRT mutation from her mother, but she had nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene.
In patient RT (RJK 951) with gout (HRH; 300323), Gibbs et al. (1989) found deletion of 13 nucleotides of which the first was 12 nucleotides 5-prime to the initiation codon in the HPRT gene. With the loss of the first nucleotide of the initiation codon, initiation in-frame may have occurred downstream.
In patient MG (RJK1780) with LNS (300322), Gibbs et al. (1990) found deletion of exon 2.
In patient EB (RJK849) with LNS (300322), Yang et al. (1984) found deletion of exons 4 to 9, inclusive. No mRNA was found.
In patient EB (RJK984) with LNS (300322), Stout and Caskey (1985) and Gibbs et al. (1990) demonstrated deletion of exons 6 to 9, inclusive. No mRNA was demonstrable.
Using restriction fragment and Southern blot analysis, Yang et al. (1984) predicted a partial HPRT gene deletion including exons 7, 8, and 9 in cell line GM3467 from a patient with LNS (300322). By multiplex amplification of the HPRT locus, Gibbs et al. (1990) demonstrated deletion of exon 9 and the presence of exons 7 and 8 in this patient.
In patient BM (RJK853) with LNS (300322), Yang et al. (1984) and Gibbs et al. (1990) found deletion of the entire HPRT gene. Deletion of the entire gene was found also in a female patient with LNS (Ogasawara et al., 1989). No mRNA was present in either case.
In patient CW (RJK866) with LNS (300322), Gibbs et al. (1989) found insertion of a single guanine nucleotide at about nucleotide 207 of the cDNA. The resulting frameshift produced a protein with 84 amino acids.
In GM2227 from a patient with LNS (300322), Edwards and Caskey (1990) found a complex rearrangement involving inversion and deletion of exons 6 to 9. No mRNA was found.
In GM1662 and GM6804 from patients with LNS (300322), Yang et al.(1984, 1988) found a complex rearrangement involving duplication of exons 2 and 3 and deletion of intron 1. Increased size of mRNA was observed. Monnat et al. (1992) demonstrated that the duplication in GM6804 was generated by the nonhomologous insertion of duplicated HPRT DNA into HPRT intron 1. They found that the duplication was genetically unstable and had a reversion rate approximately 100-fold higher than the rate of duplication formation. Exons 2 and 3, together with 13.7 kb of surrounding HPRT sequence, were duplicated.
In a patient with urate overproduction and gout (HRH; 300323), Gordon et al. (1990) found a C-to-T transition which predicted an amino acid substitution of isoleucine for threonine at amino acid 168 of the HPRT protein. The nucleotide substitution created a BamHI site, confirming a RFLP previously observed in this patient. In red cell lysates, the patient had approximately 10% of normal HPRT activity and 26% of immunoidentical HPRT protein.
In a patient with partial HPRT deficiency (enzyme activity less than 0.1%; 300323), Sculley et al. (1991) identified a G-to-A mutation at nucleotide 145 resulting in a substitution of serine for glycine-16.
In a patient with partial HPRT deficiency (enzyme activity = 10%; 300323), Sculley et al. (1991) identified a G-to-A mutation at nucleotide 271 resulting in a substitution of arginine for glycine-58.
In a patient with partial HPRT deficiency (enzyme activity = 10%; 300323), Sculley et al. (1991) found a C-to-G mutation at nucleotide 331 resulting in substitution of valine for leucine-78.
In a patient with Lesch-Nyhan syndrome (300322), Gordon et al. (1991) demonstrated a G-to-A transition in the first nucleotide of intron 6 resulting in deletion of the 83 bp comprising exon 6.
In a patient with Lesch-Nyhan syndrome (300322), Gordon et al. (1991) identified an insertion of a T nucleotide at either nucleotide 14823 or 14824. This placed a stop codon in frame, resulting in premature termination of translation of the HPRT mRNA.
Snyder et al. (1989) described 3 brothers who developed acute gouty arthritis (HRH; 300323) between ages 16 and 26 years. One brother had an episode of renal failure at the age of 5 and one suffered an attack of renal colic at age 12. None had evidence of neurologic disturbance but the youngest had epileptic episodes. Lymphoblasts established from these patients had detectable, but less than 2%, HPRT activity. Lightfoot et al. (1992) demonstrated an A-to-G transition at base 155 in exon 3 predicting a change in aspartic acid 52 to glycine.
In a Japanese patient with Lesch-Nyhan syndrome (300322), Fujimori et al. (1991, 1992) found a G-to-A transition at nucleotide 419 which predicted a single amino acid substitution of an aspartic acid for a glycine at position 140. The amino acid substitution was located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region.
Snyder et al. (1984) described a family in which 4 males had gout with partial HPRT deficiency (HRH; 300323) and reduced affinity of the enzyme for PPRP. The proband was a slow learner and stutterer, but none of the 4 had major neurologic abnormalities. One had died of renal failure, presumably due to gouty kidney at age 32. Called HPRT-Moose Jaw, the mutation in this Canadian family was due to a C-to-G transversion at nucleotide 582 (relative to initiation of translation) resulting in substitution of aspartate-194 by glutamate. Lightfoot et al. (1994) demonstrated that the K(m) of the mutant protein for hypoxanthine was increased 12-fold and the apparent K(m) for PPRP was increased 44-fold. Although the turnover number or k(cat) of the mutant protein was equivalent to that of the wildtype, the catalytic efficiency of the purified mutant protein was only 6% and 3% of that of the wildtype with hypoxanthine and PPRP, respectively.
Van Bogaert et al. (1992) described a typical case of Lesch-Nyhan syndrome (300322) in a female patient. Aral et al. (1996) demonstrated that the molecular basis of HPRT deficiency in this patient was a previously undescribed nucleotide substitution in exon 6. The gene, designated HPRT Paris, showed a single nucleotide substitution from T to G at base position 558, changing tyrosine-153 (TAT) to a stop codon (TAG). The mother showed a normal HPRT sequence, indicating that the mutation arose through a de novo gametic event. Allele-specific amplification of exon 6 confirmed the single-base substitution and showed that the patient was heterozygous. Investigation of X-chromosomal inactivation by comparison of the methylation patterns of the patient's DNA indicated a nonrandom pattern of X-chromosomal inactivation with preferential inactivation of the maternal allele. Thus, the authors concluded that the lack of HPRT activity in this female patient was the result of a de novo point mutation in the paternal gene combined with selective inactivation of the maternal gene.
In 2 Japanese patients with Lesch-Nyhan syndrome (300322), Mizunuma et al. (2001) detected the identical large genomic deletion, which spanned from an Alu sequence in a promoter region to another Alu sequence in intron 1, a length of 2,969 basepairs including exon 1. They concluded that this identical deletion in the HPRT1 gene in 2 patients was derived from recurrent events of genomic recombination, since mitochondrial DNA showed differences in the 2 cases. Mitochondrial DNA was considered a valid gauge, since HPRT1 mutations and mitochondrial DNA cotransmitted from carrier mother to offspring. The same Alu-mediated deletion of HPRT1 had not been reported among somatic mutations at this locus, suggesting that the region of the HPRT1 gene flanked by Alu sequences is a mutation hotspot in the germline but not in somatic cells.
In a 12-year-old boy with partial HPRT deficiency (HRH; 300323) who presented with recurrent acute renal failure from hyperuricemia and had no phenotypic features of Lesch-Nyhan syndrome, Srivastava et al. (2002) identified a C-to-T transition at nucleotide 193 in exon 3 of the HPRT gene, resulting in a leu65-to-phe substitution. Red blood cell lysates had less than 10% of normal HPRT activity.
In 9 patients from 7 unrelated families with the neurologic variant of Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a 143G-A transition in the HPRT gene, resulting in an arg48-to-his (R48H) substitution in an alpha-2 helix at the interface between dimerization of the protein. An additional patient with hyperuricemia and impulsive/oppositional behavior, whom the authors classified as having HPRT-related hyperuricemia (HRH; 300323), also carried the mutation. The mutation likely arose independently multiple times, because it occurred at a CpG motif. There was almost no detectable HPRT enzyme activity in patient erythrocytes, but there was some residual activity in patient fibroblasts. Kinetic studies in E. coli showed that the mutant enzyme had normal affinity for hypoxanthine and guanine, but V(max) was decreased by 33% and 37% for those substrates, respectively, compared to wildtype. However, additional studies showed that the mutant protein had poor thermal stability, with only 16% residual activity at 37 degrees C and undetectable activity at 55 degrees C, which may have explained the variable phenotypic consequences in mutation carriers.
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