HGNC Approved Gene Symbol: APRT
SNOMEDCT: 124274002, 65791008;
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38): 16:88,809,339-88,811,928 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | Adenine phosphoribosyltransferase deficiency | 614723 | Autosomal recessive | 3 |
The APRT gene encodes adenine phosphoribosyltransferase (EC 2.4.2.7), an enzyme that catalyzes the formation of AMP from adenine and phosphoribosylpyrophosphate. APRT acts as a salvage enzyme for the recycling of adenine into nucleic acids (summary by Broderick et al., 1987).
Wilson et al. (1986) determined the amino acid sequence of the APRT protein. The enzyme has 179 residues with a calculated molecular weight of 19.5 kD.
Broderick et al. (1987) determined the nucleotide sequence of the human APRT gene. The APRT gene encodes a 180-amino acid protein (Tischfield and Ruddle, 1974). Comparative analysis by Broderick et al. (1987) showed that the amino acid sequence is highly conserved: the human protein was 82% and 90% identical to the mouse and hamster sequences, respectively. The gene is constitutively expressed and subject to little, if any, regulation.
Hidaka et al. (1987) prepared a complete sequence of the APRT gene and found a number of discrepancies from the sequence reported by Broderick et al. (1987), all occurring within noncoding regions.
Broderick et al. (1987) determined that the APRT gene is about 2.6 kb long and contains 5 exons. The promoter region of the human APRT gene, like that of several other housekeeping genes, lacks the 'TATA' and 'CCAAT' boxes but contains 5 GC boxes that are potential binding sites for the Sp1 transcription factor. Broderick et al. (1987) found that CpG dinucleotides in the APRT gene in species as widely separated in evolution as man, mouse, hamster, and E. coli were conserved at a frequency higher than expected on the basis of randomness considering the G+C content of the gene. This suggested some importance of this sequence to the function of the gene. Although the intron 1 sequences of mouse and man had no apparent homology, both had retained a very high CpG content.
By cell hybridization studies, Tischfield and Ruddle (1974) concluded that the APRT locus is on chromosome 16. Marimo and Giannelli (1975) confirmed this assignment by demonstrating a 1.69-fold increase in enzyme level in trisomy 16 cells. The same cells showed no difference in the levels of HGPRT (308000), G6PD (305900) or adenosine kinase (102750) from controls.
Barg et al. (1982) assigned APRT to chromosome 16pter-q12. Lavinha et al. (1984) assigned APRT and DIA4 (125860) to 16q12-q22 by study of rearranged chromosomes 16 in somatic cell hybrids. For APRT, Ferguson-Smith and Cox (1984) found a smallest region of overlap (SRO) of 16q22.2-q22.3.
Fratini et al. (1986) mapped the APRT locus with respect to the HP (140100) locus and the fragile site at 16q23.2 (FRA16D). A subclone of the APRT gene and a cDNA clone of HP were used for molecular hybridization to DNA from mouse-human hybrid cell lines containing specific chromosome 16 translocations. The APRT subclone was used for in situ hybridization to chromosomes expressing FRA16D. APRT was found to be distal to HP and FRA16D and was localized at 16q24, making the gene order cen--FRA16B--HP--FRA16D--APRT--qter.
Mutant forms of adenine phosphoribosyltransferase resulting in enzyme deficiency (APRTD; 614723) were described by Kelley et al. (1968) and by Henderson et al. (1969), who found the inheritance to be autosomal. A heat-stable enzyme allele had a frequency of about 15% and the heat-labile enzyme allele a frequency of about 85%. Kelley et al. (1968) found apparent heterozygosity in 4 persons in 3 generations of a family. However, the level of enzyme activity ranged from 21 to 37%, not 50%.
In a lymphoblastoid cell line from a Caucasian patient in Belgium with complete APRT deficiency (614723), Hidaka et al. (1987) identified compound heterozygosity for 2 mutations in the APRT gene (102600.0001 and 102600.0002). Gathof et al. (1991) identified homozygosity for an APRT mutation (102600.0002) in identical twin brothers born to nonconsanguineous German parents with APRT deficiency. In 5 patients from Iceland with complete APRT deficiency, Chen et al. (1990) identified a homozygous mutation in the APRT gene (D65V; 102600.0004).
In Japanese, partial deficiency of APRT leads to 2,8-dihydroxyadenine urolithiasis (type II), whereas all Caucasian patients with 2,8-DHA urolithiasis have been completely deficient (type I). Fujimori et al. (1985) found that partially purified enzyme from Japanese families has a reduced affinity for phosphoribosylpyrophosphate (PRPP), as well as increased resistance to heat and reduced sensitivity to the stabilizing effect of PRPP. They referred to this common Japanese mutant allele as APRT*J. In Japanese patients with APRT deficiency, Hidaka et al. (1988) identified the molecular basis for the APRT*J allele: an M136T (102600.0003) substitution in the putative PRPP-binding site. The mutant enzyme showed abnormal kinetics and activity that was less than 10.3% of normal. By a specific cleavage method using cyanogen bromide (BrCN) to identify the M136T allele, Kamatani et al. (1989) found that 79% of all Japanese patients with APRT deficiency and more than half of the world's patients have this particular mutation.
Hakoda et al. (1990) made the interesting observation that 2-step mutations leading to homozygous deficiencies at the somatic cell level, as proposed by the Knudson hypothesis of carcinogenesis in retinoblastoma (180200) and some other human tumors, occur at other autosomal loci. They cloned and enumerated somatic T cells with mutations at the APRT locus by taking advantage of the presence of heterozygous APRT deficiency and an effective selection procedure for homozygosity. They cultured peripheral blood mononuclear cells with 2,6-diaminopurine, an APRT-dependent cytotoxin, to search for in vivo mutational cells. In all 4 heterozygotes studied, homozygously deficient T cells were found, at an average frequency of 1.3 x 10(-4). Among 310 normal persons, Hakoda et al. (1990) identified only 1 homozygous APRT-deficient clone, with a calculated frequency of 5.0 x 10(-9). Homozygous cells were found at rather high frequencies in 15 putative heterozygotes, as reported by Hakoda et al. (1991). Analysis of genomic DNA in 82 resistant clones from 2 of the heterozygotes showed that 64 (78%) had lost the germinally intact alleles. This approach may prove useful for identifying heterozygotes for other enzyme deficiencies.
Wang et al. (1999) described a Czech patient with Morquio syndrome (253000) who also had deficiency of APRT leading to 2,8-dihydroxyadenine urolithiasis. They pointed out that both GALNS (612222) and APRT are located on 16q24.3, suggesting that the patient had a deletion involving both genes. PCR amplification of genomic DNA indicated that a novel junction was created by the fusion of sequences distal to GALNS exon 2 and proximal to APRT exon 3, and that the size of the deleted region was approximately 100 kb. The deletion breakpoints were localized within GALNS intron 2 and APRT intron 2. Several other genes, including CYBA (608508), which is deleted or mutated in an autosomal form of chronic granulomatous disease (233690), are located in the 16q24.3 region. However, PCR amplification showed that the CYBA gene was present in the proband. Fukuda et al. (1996) described a Japanese patient with a submicroscopic deletion involving GALNS and APRT in one chromosome and a point mutation (R386C; 253000.0003) in the other GALNS allele. Wang et al. (1999) concluded that these findings indicated that APRT is located telomeric to GALNS, that GALNS and APRT are transcribed in the same orientation (centromeric to telomeric), and that combined APRT/GALNS deficiency may be more common than hitherto realized.
Engle et al. (1996) used targeted homologous recombination in embryonic stem cells to produce mice that lack APRT. Mice homozygous for a null Aprt allele excreted adenine and DHA crystals in their urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds.
In a lymphoblastoid cell line from a Caucasian patient in Belgium with complete APRT deficiency (614723), Hidaka et al. (1987) identified compound heterozygosity for 2 mutations in the APRT gene: a 3-bp deletion (2179delTTC) in exon 4, resulting in the deletion of codon phe173, and a 1-bp insertion (1834insT) immediately adjacent to the splice site at the 5-prime end of intron 4 (102600.0002). This insertion led to aberrant splicing, the absence of exon 4, frameshift, and premature termination at amino acid 110. The enzyme activity was less than 1% of normal and the enzyme protein was immunologically undetectable.
For discussion of the 1-bp insertion in the APRT gene (1834insT) that was found in compound heterozygous state in a lymphoblastoid cell line from a patient with complete APRT deficiency (614723) by Hidaka et al. (1987), see 102600.0001.
In identical twin brothers born to nonconsanguineous German parents with APRT deficiency, Gathof et al. (1991) identified a homozygous 1-bp insertion in the splice donor site of intron 4 of the APRT gene (the numbering system used by Gathof et al. (1991) indicated that the insertion was between bases 1831 and 1832 or 1832 and 1833). The insertion resulted in aberrant splicing. They quoted finding of the same mutation in 2 other Caucasian patients living in the U.S., and as 1 of 2 alleles in a Belgian patient with compound heterozygous APRT mutations (Hidaka et al., 1987).
Menardi et al. (1997) demonstrated homozygosity for this common T insertion at the exon 4/intron 4 junction, resulting in the lack of exon 4 in the APRT mRNA. This common splice site mutation had always been found in association with a TaqI RFLP, leading to the proposal that this splice site mutation originated from a single event (Chen et al., 1993). However, Menardi et al. (1997) found a patient with this mutation who was negative for the TaqI RFLP. The position of this T insertion suggested it was a hotspot for mutational events (Chen et al., 1993).
This mutation has been designated APRT*J.
In Japanese patients with APRT deficiency (614723), Hidaka et al. (1988) identified a 2069T-C transition in exon 5 of the APRT gene, resulting in a met136-to-thr (M136T) substitution in the putative PRPP-binding site. The mutant enzyme showed abnormal kinetics and activity that was less than 10.3% of normal.
By a specific cleavage method using cyanogen bromide (BrCN) to identify the M136T allele, Kamatani et al. (1989) found that 79% of all Japanese patients with APRT deficiency and more than half of the world's patients have this particular mutation.
Kamatani et al. (1990) found that 24 of 39 Japanese patients with 2,8-dihydroxyadenine urolithiasis had only APRT*J alleles. They found that normal alleles occur in 4 major haplotypes, whereas all APRT*J alleles occurred in only 2. They interpreted this as meaning that all APRT*J alleles had a single origin and that this mutant sequence has been maintained for a long time, as reflected in the frequency of the recombinant alleles.
Sahota et al. (1991) described DHA-lithiasis in a Japanese patient with APRT deficiency who was heterozygous for the M136T mutation. Enzyme studies showed decreased overall activity, with decreased affinity for PRPP. Lithiasis had previously only been observed in homozygotes. The polyamine pathway is thought to be the major source of endogenous adenine in man. Whether increased polyamine synthesis could lead to increased adenine production and predispose to DHA-lithiasis in an APRT heterozygote, remained to be determined.
Among 141 defective APRT alleles from 72 different Japanese families, Kamatani et al. (1992) found the met136-to-thr mutation in 96 (68%). Thirty (21%) and 10 (7%) alleles had the TGG-to-TGA nonsense mutation at codon 98 (102600.0005) and duplication of a 4-bp sequence in exon 3 (102600.0006), respectively.
Kamatani et al. (1996) noted that the APRT*J mutation is distributed nearly uniformly on the 4 main islands of Japan and Okinawa, suggesting a very early origin. Among 955 random Japanese blood samples, 7 (0.73%) were heterozygous for the APRT*J mutation. None of 231 Taiwanese samples contained heterozygotes for this mutation, whereas 2 (0.53%) of 356 Korean samples were heterozygous. Since the APRT*J mutation was found in Koreans and Okinawans who shared ancestors only before the Yayoi era (3rd century B.C. to 3rd century A.D.), the origin of the APRT*J mutation predates 300 B.C.
In 5 patients from Iceland with complete APRT deficiency (614723), Chen et al. (1990) identified a homozygous 1350A-T transversion in exon 3 of the APRT gene, resulting in an asp65-to-val (D65V) substitution. Common ancestry could only be identified for 2 of the cases.
In 4 unrelated Japanese individuals with complete APRT deficiency (614723), Mimori et al. (1991) identified a 1453G-A transition in the APRT gene, resulting in a trp98-to-ter (Y98X) substitution.
Among 141 defective APRT alleles from 72 different Japanese families with APRT deficiency (614723), Kamatani et al. (1992) found that 10 (7%) had duplication of a CCGA sequence in exon 3. The duplication resulted in an APRT*Q0 (null) allele. Two other alleles, APRT*J (102600.0003) and trp98-to-ter (Y98X; 102600.0005), accounted for 68% and 21% mutant alleles, respectively. The different alleles with the same mutation had the same haplotype, except for APRT*J. Evidence for a crossover or a gene conversion event within the APRT gene was observed in an APRT*J mutant allele.
In 2 sisters from Newfoundland with APRT deficiency (614723), Sahota et al. (1994) identified a homozygous mutation in the APRT gene, resulting in a leu110-to-pro (L110P) substitution. One of the sisters exhibited 2,8-dihydroxyadenine urolithiasis, whereas the other was disease-free.
In a Caucasian patient with complete APRT deficiency (614723), Menardi et al. (1997) found compound heterozygosity for 2 mutations in the APRT gene: a common T insertion at the IVS4 splice donor site (102600.0002) and a novel complex mutation involving simultaneous deletion/insertion and repair events. The second mutation involved a deletion of 254 bp and an insertion of 8 bp exactly at the site of the deletion. Downstream of the mutations, Menardi et al. (1997) found a 14-bp sequence of inverse complementary to this insertion and 6 flanking nucleotides. A more detailed analysis of the region where the deletion had occurred revealed several informative sequence features suitable to explain how the mutation took place.
In a Japanese man with APRT deficiency (614723), Taniguchi et al. (1998) found that the physiologic stop codon of the gene, TGA, was replaced by TCA. This base substitution generated a new HinfI restriction site, and, using PCR and subsequent digestion by this enzyme, they could confirm that the patient was homozygous for the base substitution. The amount of mRNA in transformed B cells was approximately one-quarter of that in control subjects, and no APRT proteins were detected. In eukaryotes, unlike prokaryotes, no rescue systems for defective polypeptide termination caused by a missing stop codon have been found. Therefore, the outcome of the defect in this patient was unclear from present knowledge about termination of polypeptide synthesis. The stop codon was changed to a serine codon and the reading frame was extended to the poly(A) addition site. The poly(A) signal AGTAAA is located 213 nucleotides downstream of the physiologic stop codon, but there are no stop codons between them (Broderick et al., 1987). The patient developed pseudoarthrosis after a traumatic broken arm, and was found to have increased serum creatinine and 2,8-dihydroxyadenine crystals in his urine. Imaging showed a small right kidney.
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