Pharmacy World and Science

, Volume 16, Issue 2, pp 55–61 | Cite as

Molecular biology of AMP deaminase deficiency

  • Manfred Gross
Purine and Pyrimidine Metabolism


In man, there are at least four isoforms of adenosine monophosphate deaminase (AMPD): myoadenylate deaminase in skeletal muscle, the L isoform in liver, and the E1 and E2 isoforms in erythrocytes. Myoadenylafe deaminase is encoded by the AMPD1 gene located on chromosome 1 p13-p21, the L isoform by the AMPD2 gene, and both isoforms in erythrocytes by the AMPD3 gene. Myoadenylate deaminase deficiency is found in 2–3% of all muscle biopsies. The inborn type of myoadenylate deaminase deficiency is caused by a single mutant allele harbouring two mutations: C34→T (Gin→Stop) and C143→T (Pro-48→Leu). Population studies revealed a frequency of the mutant allele of 0.12 in Caucasian Americans and Germans. The C34→T mutation is located in exon 2, which is alternatively spliced in part of the AMPD1 transcript in human muscle. Since the second mutation does not affect enzyme function, alternatively spliced mRNA encodes a catalytically active enzyme. Only one patient with a disorder linked to liver AMPD has been described so far. In this patient the decreased inhibition of this enzyme by GTP resulted in uric acid overproduction and gout. A complete lack of erythrocyte AMPD activity is found in asymptomatic subjects. The molecular basis of both disorders is not yet known.


AMP deaminase/deliciency Deficiency diseases Genetics, biochemical Mutation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lowenstein J, Tornheim K. Ammonia production in muscle: the purine nucleotide cycle. Science 1971;171:397–400.PubMedGoogle Scholar
  2. 2.
    Lowenstein JM. Ammonia production in muscle and other tissues: the purine nucleotide cycle. Physiol Rev 1972;52:382–414.Google Scholar
  3. 3.
    Sabina RL, Swain JL, Holmes EW. Myoadenylate deaminase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989:1077–84.Google Scholar
  4. 4.
    Ogasawara N, Goto H, Watanabe T. Isozymes of rat brain AMP deaminase: developmental changes and characterization of five forms. FEBS Lett 1975;58:245–8.PubMedGoogle Scholar
  5. 5.
    Stankiewicz A. AMP-deaminase from human skeletal muscle. Subunit structure, amino-acid composition and metal content of the homogenous enzyme. Int J Biochem 1981;13:1177–83.PubMedGoogle Scholar
  6. 6.
    Ogasawara N, Goto H, Yamada Y, Watanabe T. Distribution of AMP deaminase isozymes in various human blood cells. Int J Biochem 1984;16:269–73.PubMedGoogle Scholar
  7. 7.
    Ogasawara N, Goto H, Yamada Y, Watanabe T, Asano T. AMP deaminase isozymes in human tissues. Biochim Biophys Acta 1982;714:298–306.PubMedGoogle Scholar
  8. 8.
    Raggi A, Ronca-Testoni S, Ronca G. Muscle AMP aminohydrolase. II. Distribution of AMP aminohydrolase, myokinase and creatine kinase activities in skeletal muscle. Biochim Biophys Acta 1969;178:619–22.PubMedGoogle Scholar
  9. 9.
    Winder WW, Terjung RL, Baldwin KM, Holloszy JO. Effect of exercise on AMP deaminase and adenylosuccinase in rat skeletal muscle. Am J Physiol 1974;227:1411–4.PubMedGoogle Scholar
  10. 10.
    Meyer RA, Terjung RL. AMP deamination and IMP reanimation in working skeletal muscle. Am J Physiol 1980;239:C32–8.PubMedGoogle Scholar
  11. 11.
    Fishbein WN, Armbrustmacher VW, Griffin JL, Davis JI, Foster WD. Levels of adenylate deaminase, adenylate kinase, and creatine kinase in frozen human muscle biopsy specimens relative to type 1/type 2 fiber distribution: evidence for a carrier state of myoadenylate deaminase deficiency. Ann Neurol 1984;15:271–7.PubMedGoogle Scholar
  12. 12.
    Fishbein WN. Myoadenylate deaminase deficiency: primary and secondary types. Toxicol Ind Health 1986;2:105–18.PubMedGoogle Scholar
  13. 13.
    Fishbein WN, Sabina RL, Ogasawara N, Holmes ES. Immunological evidence for three isoforms of AMP deaminase (AMPD) in mature skeletal muscle. Biochim Biophys Acta 1993;1163:97–104.PubMedGoogle Scholar
  14. 14.
    Ogasawara N, Goto H, Yamada Y, Watanabe T. Distribution of AMP-deaminase isozymes in rat tissues. Eur J Biochem 1978;87:297–304.PubMedGoogle Scholar
  15. 15.
    Marquetant R, Desai NM, Sabina RL, Holmes EW. Evidence for sequential expression of multiple AMP deaminase isoforms during skeletal muscle development. Proc Natl Acad Sci USA 1987;84:2345–9.PubMedGoogle Scholar
  16. 16.
    Ogasawara N, Goto H, Yamada Y. AMP deaminase isozymes in human blood cells. J Clin Chem Clin Biochem 1982;20:401.Google Scholar
  17. 17.
    Jacobs AEM, Oosterhof A, Benders AAGM, Veerkamp JH. Expression of different isoenzymes of adenylate deaminase in cultured human muscle cells. Relation to myoadenylate deaminase deficiency. Biochim Biophys Acta 1992;1139:91–5.PubMedGoogle Scholar
  18. 18.
    Kaletha K, Nowak G. Developmental forms of human skeletal-muscle AMP deaminase. The kinetic and regulatory properties of the enzyme. Biochem J 1988;249:255–61.PubMedGoogle Scholar
  19. 19.
    Sabina RL, Marquetant R, Desai NM, Kaletha K, Holmes EW. Cloning and sequence of rat myoadenylate deaminase cDNA. Evidence for tissue-specific and developmental regulation. J Biol Chem 1987;262:12397–401.PubMedGoogle Scholar
  20. 20.
    Sabina RL, Morisaki T, Clarke P, Eddy R, Shows TB, Morton CC, et al. Characterization of the human and rat myoadenylate deaminase genes. J Biol Chem 1990;265:9423–33.PubMedGoogle Scholar
  21. 21.
    Kingsmore SF, Moseley WS, Watson ML, Sabina RL, Holmes EW, Seldin MF. Long-range restriction site mapping of a syntonic segment conserved between human chromosome 1 and mouse chromosome 3. Genomics 1990;7:75–83.PubMedGoogle Scholar
  22. 22.
    Morisaki T, Sabina RL, Holmes ES. Adenylate deaminase. A multigene family in humans and rats. J Biol Chem 1990;265:11482–6.PubMedGoogle Scholar
  23. 23.
    Sabina RL, Ogasawara N, Holmes EW. Expression of three stage-specific transcripts of AMP deaminase during myogenesis. Mol Cell Biol 1989;9:2244–6.PubMedGoogle Scholar
  24. 24.
    Mineo I, Clarke PRH, Sabina RL, Holmes EW. A novel pathway for alternative splicing: identification of an RNA intermediate that generates an alternative 5′ splice donor site not present in the primary transcript of AMPD1. Mol Cell Biol 1990;10:5271–8.PubMedGoogle Scholar
  25. 25.
    Breitbar RE, Andreadis A, Nadal-Ginard B. Alternative splicing: a ubiquitous mechanism for the generation of multiple protein isoforms from single genes. Annu Rev Biochem 1987;56:467–95.PubMedGoogle Scholar
  26. 26.
    Mineo I, Holmes EW. Exon recognition and nucleocytoplasmic partitioning determine AMPD1 alternative transcript production. Mol Cell Biol 1991;11:5356–63.PubMedGoogle Scholar
  27. 27.
    Morisaki H, Morisaki T, Newby LK, Holmes EW. Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect. J Clin Invest 1993;91:2275–80.PubMedGoogle Scholar
  28. 28.
    Bausch-Jurken MT, Mahnke-Zizelman DK, Morisaki T, Sabina RL. Molecular cloning of AMP deaminase isoform L. Sequence and bacterial expression of human AMPD2 cDNA. J Biol Chem 1992;267:22407–13.PubMedGoogle Scholar
  29. 29.
    Moseley WS, Morisaki T, Sabina RL, Holmes EW, Seidin MF. AMPD-2 maps to distal mouse chromosome 3 in linkage with AMPD-2. Genomics 1990;6:572–4.PubMedGoogle Scholar
  30. 30.
    Mahnke-Zizelman DK, Sabina RL. Cloning of human AMP deaminase isoform E cDNAs. Evidence for a third AMPD gene exhibiting alternatively spliced 5′-exons. J Biol Chem 1992;267:20866–77.PubMedGoogle Scholar
  31. 31.
    Yamada Y, Goto H, Ogasawara N. Cloning and nucleotide sequence of the cDNA encoding human erythrocyte-specific AMP deaminase. Biochim Biophys Acta 1992;1171:125–8.PubMedGoogle Scholar
  32. 32.
    Fishbein WN, Armbrustmacher VW, Griffin JL. Myoadenylate deaminase deficiency: a new disease of muscle. Science 1978;200:545–8.PubMedGoogle Scholar
  33. 33.
    Shumate J, Kaiser KK, Brooke MH, Carroll JE. Myoadenylate deaminase deficiency: disease or normal variant? Neurology 1979;29:558.Google Scholar
  34. 34.
    Heffner RR. Myoadenylate deaminase deficiency. J Neuropathol Exp Neurol 1980;39:360.Google Scholar
  35. 35.
    Fishbein WN, Armbrustmacher VW, Griffin JL. Skeletal muscle adenylate deaminase, adenylate kinase, and creatine kinase in myo-adenylate deaminase deficiency and malignant hyperthermia. Clin Res 1980;28:288A.Google Scholar
  36. 36.
    Kar NC, Pearson CM. Muscle adenylate deaminase deficiency. Report of six new cases. Arch Neurol 1981;38:279–81.PubMedGoogle Scholar
  37. 37.
    Hayes DJ, Summers BA, Morgan-Hughes JA. Myoadenylate deaminase deficiency or not? Observations on two brothers with exercise-induced muscle pain. J Neurol Science 1982;53:125–36.Google Scholar
  38. 38.
    Kelemen J, Rice DR, Bradley WG, Munsat TL, DiMauro S, Hogan EL. Familial myoadenylate deaminase deficiency and exertional myalgia. Neurology 1982;32:857–63.PubMedGoogle Scholar
  39. 39.
    Goebel HH, Bardosi A. Myoadenylate deaminase deficiency. Klin Wochenschr 1987;65:1023–33.PubMedGoogle Scholar
  40. 40.
    Mercelis R, Martin JJ, de Barsy T, Van de Berghe G. Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies. J Neurol 1987;234:385–9.PubMedGoogle Scholar
  41. 41.
    Fishbein WN, Armbrustmacher VW, Griffin JL. Myoadenylate deaminase deficiency: verification on repeat biopsy, fresh or frozen, and origin of the residual enzyme. IRCS Med Sci Biochem 1981;9:103–4.Google Scholar
  42. 42.
    Gross M, Gresser U. Ergometer exercise in myoadenylate deaminase deficient patients. Clin Invest 1993;71:461–5.Google Scholar
  43. 43.
    Zöllner N, Reiter S, Gross M, Pongratz D, Reimers CD, Gerbitz K, et al. Myoadenylate deaminase deficiency: successful symptomatic therapy by high dose oral administration of ribose. Klin Wochenschr 1986;64:1281–90.PubMedGoogle Scholar
  44. 44.
    Pongratz DE, Reimers CD, Gross M, Paetzke I, Zimmer HG. Symptomatische Therapie des primären Myoadenylat-deaminase-Mangels sowie der Glykogenose Typ V mit D-Ribose. Fortschr Myologie 1987;IX:42.Google Scholar
  45. 45.
    Gross M, Reiter S, Zöllner N. Metabolism of D-ribose administered continuously to healthy persons and to patients with myoadenylate deaminase deficiency. Klin Wochenschr 1989;67:1205–13.PubMedGoogle Scholar
  46. 46.
    Gross M, Zöllner N. Serum levels of glucose, insulin and C-peptide during long-term D-ribose administration in man. Klin Wochenschr 1991;69:31–6.PubMedGoogle Scholar
  47. 47.
    Gross M, Kormann B, Zöllner N. Ribose administration during exercise: Effects on substrates and products of energy metabolism in healthy subjects and a patient with myoadenylate deaminase deficiency. Klin Wochenschr 1991;69:151–5.PubMedGoogle Scholar
  48. 48.
    Fishbein WN, Armbrustmacher VW. Primary and secondary forms of myoadenylate deaminase deficiency (MDD). Clin Res 1984;32:288A.Google Scholar
  49. 49.
    Kar NC, Pearson CM. Muscle adenylic acid deaminase activity. Selective decrease in early-onset Duchenne muscular dystrophy. Neurology 1973;23:478–82.PubMedGoogle Scholar
  50. 50.
    Nagao H, Habara S, Morimoto T, Sano N, Takahashi M, Kida K, et al. AMP deaminase activity of skeletal muscle in neuromuscular disorders in childhood. Histochemical and biochemical studies. Neuropediatrics 1986;17:193–8.PubMedGoogle Scholar
  51. 51.
    DiMauro S, Miranda AF, Hays AP, Franck WA, Hoffman GS, Schoenfeldt RS, et al. Myoadenylate deaminase deficiency. Muscle biopsy and muscle culture in a patient with gout. J Neurol Sci 1980;47:191–202.PubMedGoogle Scholar
  52. 52.
    Gross M, Morisaki T, Pongratz D, Holmes EW, Zöllner N. Normal restriction pattern (Hind III) of the myoadenylate deaminase gene in enzyme deficient patients. Klin Wochenschr 1990;68:1084.PubMedGoogle Scholar
  53. 53.
    Morisaki T, Gross M, Morisaki H, Pongratz D, Zöllner N, Holmes EW. Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci USA 1992;89:6457–61.PubMedGoogle Scholar
  54. 54.
    Sabina RL, Fishbein WN, Pezeshkpour G, Clarke PRH, Holmes EW. Molecular analysis of the myoadenylate deaminase deficiencies. Neurology 1992;42:170–9.PubMedGoogle Scholar
  55. 55.
    Youssoufian H, Kazazian JJ, Phillips DG, Aronis S, Tsiftis G, Brown VA, et al. Recurrent mutations in haemophilia A give evidence for CpG mutation hot spots. Nature 1986;324:380–2.PubMedGoogle Scholar
  56. 56.
    Sabina RL, Sulaiman AR, Wortmann RL. Molecular analysis of acquired myoadenylate deaminase deficiency in polymyositis (idiopathic inflammatory myopathy). Adv Exp Med Biol 1991;309B:203–5.PubMedGoogle Scholar
  57. 57.
    Van den Berghe G, Hers HG. Abnormal AMP deaminase in primary gout. Lancet 1980;2:1090.Google Scholar
  58. 58.
    Hers HG, Van den Berghe G. Enzyme defect in primary gout. Lancet 1979;1:585–6.PubMedGoogle Scholar
  59. 59.
    Ogasawara N, Goto H, Yamada Y, Hasegawa I. Deficiency of erythrocyte type isozyme of AMP deaminase in human. Adv Exp Med Biol 1986;195A:123–7.Google Scholar
  60. 60.
    Ogasawara N, Goto H, Yamada Y, Nishigaki I, Itoh T, Hasegawa I, et al. Deficiency of AMP deaminase in erythrocytes. Hum Genet 1987;75:15–18.PubMedGoogle Scholar
  61. 61.
    Zydowo MM, Purzycka-Preis J, Ogasawara N. Deficiency of AMP deaminase in human erythrocytes. Adv Exp Med Biol 1990;253A:31–4.Google Scholar

Copyright information

© Royal Dutch Association for the Advancement of Pharmacy 1994

Authors and Affiliations

  • Manfred Gross
    • 1
  1. 1.Medizinischc Poliklinik der Universität MünchenMünchenGermany

Personalised recommendations