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. 1987 Nov;80(5):1409–1415. doi: 10.1172/JCI113219

Human adenine phosphoribosyltransferase. Identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme.

Y Hidaka 1, T D Palella 1, T E O'Toole 1, S A Tarlé 1, W N Kelley 1
PMCID: PMC442397  PMID: 3680503

Abstract

This study reports the first demonstration of specific mutations leading to human adenine phosphoribosyltransferase (APRT) deficiency. The molecular basis of the deficiency was investigated by determining the sequence of both alleles of a patient with a complete deficiency in APRT activity. A trinucleotide deletion, corresponding to phenylalanine on the deduced amino acid sequence, was confirmed on one allele. A single nucleotide insertion, immediately adjacent to the splice site at the 5' end of the fourth intervening sequence, was confirmed on the other allele. This insertion lead to aberrant splicing, as was demonstrated by the absence of exon 4 in the complementary DNA sequence and by altered RNase mapping analysis of the abnormal messenger RNA.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aebi M., Hornig H., Padgett R. A., Reiser J., Weissmann C. Sequence requirements for splicing of higher eukaryotic nuclear pre-mRNA. Cell. 1986 Nov 21;47(4):555–565. doi: 10.1016/0092-8674(86)90620-3. [DOI] [PubMed] [Google Scholar]
  2. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
  4. Cartier P., Hamet M., Hamburger J. Une nouvelle maladie nétabolique: le déficit complete en adénine-phosphoribosyltransférase avec lithiase de 2,8-dihydroxyadénine. C R Acad Sci Hebd Seances Acad Sci D. 1974 Sep;279(10):883–886. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. DiLella A. G., Marvit J., Lidsky A. S., Güttler F., Woo S. L. Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria. 1986 Aug 28-Sep 3Nature. 322(6082):799–803. doi: 10.1038/322799a0. [DOI] [PubMed] [Google Scholar]
  7. Farabaugh P. J., Schmeissner U., Hofer M., Miller J. H. Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli. J Mol Biol. 1978 Dec 25;126(4):847–857. doi: 10.1016/0022-2836(78)90023-2. [DOI] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  9. Fox I. H. Purine enzyme abnormalities: a four year experience. Adv Exp Med Biol. 1977;76A:265–269. doi: 10.1007/978-1-4613-4223-6_32. [DOI] [PubMed] [Google Scholar]
  10. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  11. Holden J. A., Meredith G. S., Kelley W. N. Human adenine phosphoribosyltransferase. Affinity purification, subunit structure, amino acid composition, and peptide mapping. J Biol Chem. 1979 Aug 10;254(15):6951–6955. [PubMed] [Google Scholar]
  12. Johnson L. A., Gordon R. B., Emmerson B. T. Adenine phosphoribosyltransferase: a simple spectrophotometric assay and the incidence of mutation in the normal population. Biochem Genet. 1977 Apr;15(3-4):265–272. doi: 10.1007/BF00484458. [DOI] [PubMed] [Google Scholar]
  13. Kamatani N., Terai C., Kuroshima S., Nishioka K., Mikanagi K. Genetic and clinical studies on 19 families with adenine phosphoribosyltransferase deficiencies. Hum Genet. 1987 Feb;75(2):163–168. doi: 10.1007/BF00591080. [DOI] [PubMed] [Google Scholar]
  14. Kelley W. N., Levy R. I., Rosenbloom F. M., Henderson J. F., Seegmiller J. E. Adenine phosphoribosyltransferase deficiency: a previously undescribed genetic defect in man. J Clin Invest. 1968 Oct;47(10):2281–2289. doi: 10.1172/JCI105913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kimura A., Matsunaga E., Takihara Y., Nakamura T., Takagi Y., Lin S., Lee H. Structural analysis of a beta-thalassemia gene found in Taiwan. J Biol Chem. 1983 Mar 10;258(5):2748–2749. [PubMed] [Google Scholar]
  16. Messing J. New M13 vectors for cloning. Methods Enzymol. 1983;101:20–78. doi: 10.1016/0076-6879(83)01005-8. [DOI] [PubMed] [Google Scholar]
  17. Murray A. M., Drobetsky E., Arrand J. E. Cloning the complete human adenine phosphoribosyl transferase gene. Gene. 1984 Nov;31(1-3):233–240. doi: 10.1016/0378-1119(84)90214-2. [DOI] [PubMed] [Google Scholar]
  18. O'Toole T. E., Wilson J. M., Gault M. H., Kelley W. N. Human adenine phosphoribosyltransferase: characterization from subjects with a deficiency of enzyme activity. Biochem Genet. 1983 Dec;21(11-12):1121–1134. doi: 10.1007/BF00488464. [DOI] [PubMed] [Google Scholar]
  19. Okayama H., Berg P. High-efficiency cloning of full-length cDNA. Mol Cell Biol. 1982 Feb;2(2):161–170. doi: 10.1128/mcb.2.2.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Orkin S. H., Goff S. C., Hechtman R. L. Mutation in an intervening sequence splice junction in man. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5041–5045. doi: 10.1073/pnas.78.8.5041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Orkin S. H., Goff S. C. Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes. J Biol Chem. 1981 Oct 10;256(19):9782–9784. [PubMed] [Google Scholar]
  22. Orkin S. H., Sexton J. P., Goff S. C., Kazazian H. H., Jr Inactivation of an acceptor RNA splice site by a short deletion in beta-thalassemia. J Biol Chem. 1983 Jun 25;258(12):7249–7251. [PubMed] [Google Scholar]
  23. Padgett R. A., Grabowski P. J., Konarska M. M., Seiler S., Sharp P. A. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. doi: 10.1146/annurev.bi.55.070186.005351. [DOI] [PubMed] [Google Scholar]
  24. Padgett R. A., Konarska M. M., Grabowski P. J., Hardy S. F., Sharp P. A. Lariat RNA's as intermediates and products in the splicing of messenger RNA precursors. Science. 1984 Aug 31;225(4665):898–903. doi: 10.1126/science.6206566. [DOI] [PubMed] [Google Scholar]
  25. Reed R., Maniatis T. A role for exon sequences and splice-site proximity in splice-site selection. Cell. 1986 Aug 29;46(5):681–690. doi: 10.1016/0092-8674(86)90343-0. [DOI] [PubMed] [Google Scholar]
  26. Robertson M. A., Staden R., Tanaka Y., Catterall J. F., O'Malley B. W., Brownlee G. G. Sequence of three introns in the chick ovalbumin gene. Nature. 1979 Mar 22;278(5702):370–372. doi: 10.1038/278370a0. [DOI] [PubMed] [Google Scholar]
  27. Ruskin B., Krainer A. R., Maniatis T., Green M. R. Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro. Cell. 1984 Aug;38(1):317–331. doi: 10.1016/0092-8674(84)90553-1. [DOI] [PubMed] [Google Scholar]
  28. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Simmonds H. A., Van Acker K. J., Cameron J. S., Snedden W. The identification of 2,8-dihydroxyadenine, a new component of urinary stones. Biochem J. 1976 Aug 1;157(2):485–487. doi: 10.1042/bj1570485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Srivastava S. K., Villacorte D., Beutler E. Correlation between adenylate metabolizing enzymes and adenine nucleotide levels of erythrocytes during blood storage in various media. Transfusion. 1972 May-Jun;12(3):190–197. doi: 10.1111/j.1537-2995.1972.tb00008.x. [DOI] [PubMed] [Google Scholar]
  31. Stambrook P. J., Dush M. K., Trill J. J., Tischfield J. A. Cloning of a functional human adenine phosphoribosyltransferase (APRT) gene: identification of a restriction fragment length polymorphism and preliminary analysis of DNAs from APRT-deficient families and cell mutants. Somat Cell Mol Genet. 1984 Jul;10(4):359–367. doi: 10.1007/BF01535631. [DOI] [PubMed] [Google Scholar]
  32. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tischfield J. A., Ruddle F. H. Assignment of the gene for adenine phosphoribosyltransferase to human chromosome 16 by mouse-human somatic cell hybridization. Proc Natl Acad Sci U S A. 1974 Jan;71(1):45–49. doi: 10.1073/pnas.71.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Treisman R., Orkin S. H., Maniatis T. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591–596. doi: 10.1038/302591a0. [DOI] [PubMed] [Google Scholar]
  35. Treisman R., Proudfoot N. J., Shander M., Maniatis T. A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing. Cell. 1982 Jul;29(3):903–911. doi: 10.1016/0092-8674(82)90452-4. [DOI] [PubMed] [Google Scholar]
  36. Van Acker K. J., Simmonds H. A., Potter C., Cameron J. S. Complete deficiency of adenine phosphoribosyltransferase. Report of a family. N Engl J Med. 1977 Jul 21;297(3):127–132. doi: 10.1056/NEJM197707212970302. [DOI] [PubMed] [Google Scholar]
  37. WYNGAARDEN J. B., DUNN J. T. 8-Hydroxyadenine as the intermediate in the oxidation of adenine to 2, 8-dihydroxyadenine by xanthine oxidase. Arch Biochem Biophys. 1957 Jul;70(1):150–156. doi: 10.1016/0003-9861(57)90088-7. [DOI] [PubMed] [Google Scholar]
  38. Wilson J. M., Daddona P. E., Simmonds H. A., Van Acker K. J., Kelley W. N. Human adenine phosphoribosyltransferase. Immunochemical quantitation and protein blot analysis of mutant forms of the enzyme. J Biol Chem. 1982 Feb 10;257(3):1508–1515. [PubMed] [Google Scholar]
  39. Wilson J. M., O'Toole T. E., Argos P., Shewach D. S., Daddona P. E., Kelley W. N. Human adenine phosphoribosyltransferase. Complete amino acid sequence of the erythrocyte enzyme. J Biol Chem. 1986 Oct 15;261(29):13677–13683. [PubMed] [Google Scholar]
  40. Witten F. R., Morgan J. W., Foster J. G., Glenn J. F. 2,8-dihydroxyadenine urolithiasis: review of the literature and report of a case in the United States. J Urol. 1983 Nov;130(5):938–942. doi: 10.1016/s0022-5347(17)51584-0. [DOI] [PubMed] [Google Scholar]
  41. Young R. A., Davis R. W. Efficient isolation of genes by using antibody probes. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1194–1198. doi: 10.1073/pnas.80.5.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]

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