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Abstract

Abstract 

  1. Adenine phosphoribosyltransferase (APRT) catalyzes the synthesis of AMP from adenine and 5-phosphoribosyl-1-pyrophosphate (PP-ribose-P). An inherited deficiency of this enzyme (MIM 1026000) results in inability to utilize adenine, which, in the absence of any other significant pathway of metabolism in humans, is oxidized by xanthine dehydrogenase (XDH) via the 8-hydroxy intermediate to 2,8-dihydroxyadenine (2,8-DHA). 2,8-DHA is extremely insoluble, and its accumulation in the kidney can lead to crystalluria and the formation of urinary stones. Adenine and 2,8-DHA are secreted by the human kidney, and 2,8-DHA is protein-bound in the circulation. Both these factors tend to minimize toxicity in tissues other than the kidney. Administration of exogenous adenine itself has produced 2,8-DHA nephrotoxicity in a variety of animal systems and also in humans with normal APRT activity given massive transfusions of adenine-containing blood.

  2. Clinical symptoms, which include renal colic, hematuria, urinary tract infection, and dysuria, are due to 2,8-DHA stone formation or crystalluria and may be present from birth. Age at diagnosis has ranged from 5 months to 74 years, and approximately 60 percent of patients have been male. As many as 50 percent of APRT-deficient individuals may be asymptomatic. Acute renal failure may occur as the presenting symptom and can be reversible. Some patients have developed chronic renal failure, requiring dialysis or transplantation, and in a subset of these, 2,8-DHA crystals were first detected during biopsy analysis of the native or the transplanted kidney. Homozygotes do not show any evidence of immunodeficiency.

  3. Except for the excretion of adenine and its metabolites, no biochemical abnormalities have been recorded. Purine production and excretion are normal, indicating that, unlike the companion enzyme hypoxanthine-guanine phosphoribosyltransferase, APRT is not vital for the overall control of purine metabolism in humans. Adenine metabolites in the urine account for 20–30 percent of total purine excretion, even on a low-purine diet. The main source of endogenous adenine is probably polyamine synthesis, of which adenine is a metabolic byproduct. Adenine-rich foods may be a contributing factor in precipitating urolithiasis.

  4. Two types of APRT deficiency have been recognized, based on the level of residual enzyme activity in erythrocyte lysates. Patients with type I deficiency have no detectable activity in erythrocyte lysates. Approximately 140 such patients have been identified in many countries, including 45 in Japan. These patients are homozygotes or compound heterozygotes for null alleles. Patients with type II deficiency have significant enzyme activity (5–25 percent of wild-type in hemolysates) and have been found only in Japan to date (138 cases). Approximately 75 percent of the patients in Japan have the type II defect. The type II enzyme has reduced affinity for PP-ribose-P compared with the wild-type enzyme. In both types of deficiency, APRT activity is neither demonstrable in intact cells nor functional in vivo. Intact cells are resistant to the toxic effects of 2,6-diaminopurine (DAP) and other adenine analogues that depend on APRT for their metabolism.

  5. APRT deficiency is inherited in an autosomal recessive manner. The frequency of heterozygosity is quite high (0.4–1.2 per 100), but the number of identified cases is smaller than expected, especially in non-Japanese populations. This may be due to the wide variability in the clinical expression of the defect, coupled with problems of diagnosis.

  6. Heterozygotes for the type I or type II defect do not appear to have any clinical or biochemical abnormalities. Intact cells from both types of heterozygote incorporate significant amounts of adenine into nucleotides and are sensitive to DAP, and APRT activity is detectable in hemolysates. Thus, the two types of heterozygote cannot readily be distinguished from each other by assays in intact cells or in cell extracts. The distinction can be made by culturing peripheral blood lymphocytes from these individuals in DAP, isolating DAP-resistant colonies, and carrying out APRT assay in cell extracts. Both types of heterozygote give rise to DAP-resistant colonies, but only colonies from type II heterozygotes have enzyme activity. Type I and type II heterozygotes can also be distinguished by starch gel electrophoresis.

  7. APRT is a dimer with 179 amino acid residues per subunit and a subunit molecular weight of 19,481. The APRT gene is located on chromosome 16q24.3 and encompasses 2.8 kb of genomic DNA. The gene is similar in size and intron-exon arrangement to the rodent genes and has five exons and four introns. Fourteen polymorphisms have been identified in the immediate 5′ and 3′ flanking regions of the gene. Other polymorphisms include two TaqI sites and a BglII site within the gene and an SphI site upstream. Most of the polymorphisms have been detected in both Japanese and non-Japanese subjects.

  8. The molecular basis of APRT deficiency has been determined in many patients by sequence analysis of genomic DNA amplified by the polymerase chain reaction (PCR). Fifteen mutations have been identified in non-Japanese patients. Nine of these were single base substitutions, two were single base-pair insertions, three were small deletions (2–7 bp), and one was a complex mutation. At least three mutations appeared to have common ancestral origins. Three mutations accounted for 95 percent of the mutant alleles identified in Japanese patients. These were the M136T missense mutation (67 percent), observed exclusively in type II patients, and the W98X nonsense mutation (21 percent) and a 4-bp duplication in exon 3 (7 percent), each found in both type I and type II patients. Approximately 79 percent of type II patients are homozygous for the M136T mutation, the remainder being compound heterozygotes with an M136T/null genotype.

  9. The nature of spontaneous somatic mutations (“second hits”) affecting the normal allele in APRT heterozygotes has been determined by studying DAP-resistant T cell clones. In approximately 75 percent of the DAP-resistant clones, there was loss of the wild-type allele and flanking markers (loss of heterozygosity) due to mitotic recombination. The remaining clones contained point mutations or other minor structural changes within the wild-type alleles, and the nature of these mutations was similar to those observed in the germline.

  10. In the past, 2,8-DHA stones were generally confused with uric acid stones, because of their identical chemical reactivity. Correct identification requires UV, IR, MS, x-ray crystallography, HPLC, or capillary electrophoresis. The presence of brownish spots on the diaper or of yellow-brown, round crystals in the urine in both symptomatic and asymptomatic individuals is suggestive of APRT deficiency. The diagnosis may be confirmed by the identification of adenine and 2,8-DHA in the urine, together with the absence of functional APRT activity in intact erythrocytes. The latter will be impossible to establish if a recent transfusion has formed an essential part of the therapy.

  11. Treatment has included dietary purine restriction and high fluid intake. Allopurinol administration has prevented further 2,8-DHA excretion and stone formation. The use of alkali should be avoided. Renal transplantation has been successful in several patients. Shock-wave lithotripsy has been beneficial in a small number of patients.

  12. Homozygous APRT-deficient mice have been produced by targeted homologous recombination in embryonic stem cells. The APRT knockout mice appear to be a faithful model for human APRT deficiency. These mice excrete adenine and 2,8-DHA crystals in the urine, and renal histopathology shows extensive tubular dilatation, inflammation, necrosis, and fibrosis that varies in severity with the mouse background.

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