Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mice lacking tissue non–specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B–6

Nature Genetics volume 11, pages 45–51 (1995)Cite this article

Abstract

In humans, deficiency of the tissue non-specific alkaline phosphatase (TNAP) gene is associated with defective skeletal mineralization. In contrast, mice lacking TNAP generated by homologous recombination using embryonic stem (ES) cells have normal skeletal development. However, at approximately two weeks after birth, homozygous mutant mice develop seizures which are subsequently fatal. Defective metabolism of pyridoxal 5′-phosphate (PLP), characterized by elevated serum PLP levels, results in reduced levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain. The mutant seizure phenotype can be rescued by the administration of pyridoxal and a semi-solid diet. Rescued animals subsequently develop defective dentition. This study reveals essential physiological functions of TNAP in the mouse.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. McComb, R.B., Bowers Jr, G.N. & Posen, S. Alkaline Phosphatase (Plenum Press, New York, NY, 1979).

    Book  Google Scholar 

  2. Low, M.G. & Saltiel, A.R. Structural and functional roles of glycosyl-phosphatidylinositol in membranes. Science 239, 268–275 (1988).

    Article  CAS  Google Scholar 

  3. Henthom, P.S., Raducha, M., Kadesch, T., Weiss, M.J. & Harris, H. Sequence and characterization of the human intestinal alkaline phosphatase gene. J. biol. Chem. 263, 12011–12019 (1988).

    Google Scholar 

  4. Knoll, B.J., Rothblum, K.N. & Longley, M. Nucleotide sequence of the human placental alkaline phosphatase gene. Evolution of the 5′ flanking region by deletion/substitution J. biol. Chem. 263, 12020–12027 (1988).

    CAS  PubMed  Google Scholar 

  5. Millán, J.L. & Manes, T. Seminoma-derived Nagao isozyme is encoded by a germ-cell alkaline phosphatase gene. Proc. natn. Acad. Sci. U.S.A. 85, 3024–3028 (1988).

    Article  Google Scholar 

  6. Weiss, M.J. et al. Structure of the human liver/bone/kidney alkaline phosphatase gene. J. biol. Chem. 263, 12002–12010 (1988).

    CAS  PubMed  Google Scholar 

  7. Manes, T., Glade, K., Ziomek, C.A. & Millán, J.L. Genomic structure and comparison of mouse tissue-specific alkaline phosphatase genes. Genomics 8, 541–554 (1990).

    Article  CAS  Google Scholar 

  8. Hahnel, A.C. et al. Two alkaline phosphatase genes are expressed during early development in the mouse embryo. Development 110, 555–564 (1990).

    CAS  Google Scholar 

  9. Hahnel, A.C. & Schultz, G.A. Cloning and characterization of a cDNA encoding alkaline phosphatase in mouse embryonal carcinoma cells. Clinica Chim. Acta 186, 171–174 (1989).

    Article  Google Scholar 

  10. MacGregor, G.R., Zambrowicz, B.P. & Soriano, P. Tissue non-specific alkaline phosphatase is expressed in both embryonic and extra-embryonic lineages during mouse embryogenesis but is not required for migration of primordial germ cells. Development 121, 1487–1496 (1995).

    CAS  PubMed  Google Scholar 

  11. Terao, M. & Mintz, B. Cloning and characterisation of a cDNA coding for mouse placental alkaline phosphatase. Proc. natn. Acad. Sci. U.S.A. 84, 7051–7055 (1987).

    Article  CAS  Google Scholar 

  12. Henthorn, P.S., Raducha, M., Fedde, K.N., Lafferty, M.A. & Whyte, M.P. Different missense mutations at the tissue non-specific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc. natn. Acad. Sci. U.S.A. 89, 9924–9928 (1992).

    Article  CAS  Google Scholar 

  13. Whyte, M.P. in The Metabolic Basis of Inherited Disease, 7th Edition. (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 4095–4111 (McGraw-Hill, New York, 1995).

    Google Scholar 

  14. Whyte, M.P., Teitelbaum, S.L., Murphy, W.A., Bergfeld, M.A. & Avioli, L.V. Adult hypophosphatasia: clinical, laboratory and genetic investigation of a large kindred with review of the literature. Medicine 58, 329–347 (1979).

    Article  CAS  Google Scholar 

  15. Whyte, M.P., Murphy, W.M. & Fallen, M.D. Adult hypophosphatasia with chondrocalcinosis and arthropathy : Variable penetrance of hypophosphatasemia in a large Oklahoma kindred. Am. J. Med. 72, 631–641 (1982).

    Article  CAS  Google Scholar 

  16. Macfarlane, J.D., Kroon, H.M. & van der Harten, J.J. Phenotypically dissimilar hypophosphatasia in two sibships. Am. J. med. Genet. 42, 117–121 (1992).

    Article  CAS  Google Scholar 

  17. Ritchie, G.M. Hypophosphatasia: a metabolic disease with important dental manifestations. Arch. Dis. Child. 39, 584–590 (1964).

    Article  CAS  Google Scholar 

  18. Houpt, M.I., Kenny, F.M. & Listgarten, M. Hypophosphatasia: case reports. J. Dent Child. 27, 126–137 (1970).

    Google Scholar 

  19. Bruckner, R.J., Rickles, N.H. & Porter, D.R. Hypophosphatasia with premature shedding of teeth and aplasia of cementum. Oral Path. 15, 1351–1369 (1962).

    Article  CAS  Google Scholar 

  20. Rasmussen, K. Phosphorylethanolamine and hypophosphatasia. Danish Medical Bulletin 15, 1–112 (1968).

    Google Scholar 

  21. Whyte, M.P. et al. Perinatal hypophosphatasia: tissue levels of vitamin B-6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5′-phosphate. J. Clin. Invest. 81, 1234–1239 (1988).

    Article  CAS  Google Scholar 

  22. Takahashi, T. et al. in Endocrine control of bone and calcium metabolism. (eds Chon, D.V., Fugita, T., Potts, J.T.J. & Talmage, R.V.) 93–94 (Excerpta Medica, Amsterdam, 1984).

    Google Scholar 

  23. Roxburgh, S.T.D. Atypical retinitis pigmentosa with hypophosphatasia. Trans. ophthal. Soc. U.K. 103, 513–516 (1983).

    Google Scholar 

  24. Warshaw, J.B., Littlefield, J.W., Fishman, W.H., Inglis, N.R. & Stolbach, L.L. Serum alkaline phosphate in hypophosphatasia. J. din. Invest. 50, 2137–2142 (1971).

    CAS  Google Scholar 

  25. Ornoy, A., Adomian, G.E. & Rimoin, D.L. Histologic and ultrastructural studies on the mineralisation process in hypophosphatasia. Am. J. Med. Genet. 22, 743–758 (1985).

    Article  CAS  Google Scholar 

  26. Whyte, M.P., Mahuren, J.D., Vrabel, L.A. & Cobum, S.P. Markedly increased circulating pyridoxal 5′-phosphate levels in hypophosphatasia. J. Clin. Invest. 76, 752–756 (1985).

    Article  CAS  Google Scholar 

  27. Snell, E.E. & Haskell, B.E. in Comprehensive Biochemistry. (eds Florkin, M. & Stotz, E.H.) 47–71 (Elsevier, Amsterdam, 1971).

    Google Scholar 

  28. Fedde, K.N., Cole, D.E. & Whyte, M.P. Pseudohypophosphatasia: aberrant localization and substrate specificity of alkaline phosphatase in cultured skin fibrobiasts. Am. J. hum. Genet. 47, 776–783 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Fedde, K.N. & Whyte, M.P. Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal 5′-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study. Am. J. hum. Genet. 47, 767–775 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Fonda, M.L., Eggers, D.K., Auerbach, S. & Fritsch, L. Vitamin B-6 metabolism in the brains of young adult and senescent mice. Exp. Geront. 15, 473–479 (1980).

    Article  CAS  Google Scholar 

  31. Bukin, Y.V. Pyridoxal kinase activity and content of pyridoxal phosphate in mammalian tissues under normal and some experimental conditions. Biokhimiya 41, 81–90 (1976).

    CAS  Google Scholar 

  32. Shideler, C.E. Vitamin B-6: an overview. Am. J. med. Tech. 49, 17–22 (1983).

    CAS  Google Scholar 

  33. Voet, D. & Voet, J.G. Biochemistry. (Wiley, New York, 1990).

  34. Meldrum, B.S. Epilepsy and γ-aminobutyric acid-mediated inhibition. Int. Rev. Neurobiol. 17, 1–36 (1975).

    Article  CAS  Google Scholar 

  35. Dakshinamurti, K. & Stephens, M.C. Pyridoxine deficiency in the neonatal rat. J. Neurochem. 16, 1515–1522 (1969).

    Article  CAS  Google Scholar 

  36. Stephens, M.C., Havlicek, V. & Dakshinamurti, K. Pyridoxine deficiency and development of the central nervous system in the rat. J. Neurochem. 18, 2407–2416 (1971).

    Article  CAS  Google Scholar 

  37. Guilarte, T.R. Regional changes in the concentrations of glutamate, glycine, taurine and GABA in the vitamin B-6 deficient developing rat brain: association with neo-natal seizures. Neurochem. Res. 14, 889–897 (1989).

    Article  CAS  Google Scholar 

  38. Wasynczuk, A., Kirksey, A. & Morre, D.M. Effects of maternal vitamin B-6 deficiency on specific regions of developing rat brain : the extrapyramidal motor system. J. Nutrition 113, 746–754 (1983).

    Article  CAS  Google Scholar 

  39. Ebadi, M. Regulation and function of pyridoxal phosphate in CNS. Neurochem. Intl. 3, 181–206 (1981).

    Article  CAS  Google Scholar 

  40. Bayoumi, R.A. & Smith, W.R.D. Someeffectsof dietary vitamin B-6 deficiency on γaminobutyric acid metabolism in developing rat brain. J. Neurochem. 19, 1883–1897 (1972).

    Article  CAS  Google Scholar 

  41. Eastman, C.L. & Guilarte, T.R. Vitamin B-6, kynurenines and central nervous system function : developmental aspects. J. Nutr. Biochem. 3, 618–631 (1992).

    Article  CAS  Google Scholar 

  42. Caswell, A.M., Whyte, M.P. & Russell, R.G.G. Hypophosphatasia and the extracellular metabolism of inorganic pyrophosphate: clinical and laboratory aspects. Crit. Rev. din. Lab. Sci. 28, 175–232 (1991).

    Article  CAS  Google Scholar 

  43. Wada, H. & Snell, E.E. The enzymatic oxidation of pyridoxine and pyridoxamine phosphates. J. biol. Chem. 236, 2089–2095 (1961).

    CAS  PubMed  Google Scholar 

  44. Krinke, G., Naylor, D.C. & Skorpil, V. Pyridoxine vitaminosis: an analysis of the early changes induced with massive doses of vitamin B-6 in rat primary sensory neurons. J. Neuropathol. exp. Neurol. 44, 117–129 (1985).

    Article  CAS  Google Scholar 

  45. Krinke, G. et al. Pyridoxine megavitaminosis produces degeneration of peripheral sensory neurons in the dog. Neurotoxicology 2, 13–24 (1980).

    Google Scholar 

  46. Albin, R.L. et al. Acute sensory neuropathy—neuronopathy from pyridoxine overdose. Neurology 37, 1729–1732 (1987).

    Article  CAS  Google Scholar 

  47. Salhany, J.M. & Schopfer, L.M. Pyridoxal 5′-phosphate binds specifically to soluble CD4 protein, the HIV-1 receptor. J. biol. Chem. 268, 7643–7645 (1993).

    CAS  PubMed  Google Scholar 

  48. Salhany, J.M., Rauenbuehler, P.B. & Sloan, R.L. Characterisation of pyridoxal 5′-phosphate affinity labelling of band 3 protein. J. biol. Chem. 262, 15965–15973 (1987).

    CAS  PubMed  Google Scholar 

  49. Langman, M.J.S. et al. Influence of diet on the intestinal component of serum alkaline phosphatase in people of different ABO blood groups and secretor status. Nature 212, 41–43 (1966).

    Article  CAS  Google Scholar 

  50. Gould, B.S. The nature of the increased serum phosphatase in rats after fat feeding. Arch. Biochem. 4, 175–181 (1944).

    CAS  Google Scholar 

  51. Whyte, M.P. et al. Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyse phosphoethanolamine, inorganic pyrophosphate and pyridoxal 5′-phosphate. J. Clin. Invest. 95, 1440–1445 (1995).

    Article  CAS  Google Scholar 

  52. Friedrich, G.A. & Soriano, P. Promoter traps in embryonic stem cells: genetic screen to identify and mutate developmental genes in mice. Genes Dev. 5, 1513–1523 (1990).

    Article  Google Scholar 

  53. Slocum, R.H. & Cummings, J.G. in Techniques in diagnostic human biochemical genetics: a laboratory manual. (ed. Hommes, F.A.) 87–128 (Wiley-Liss, 1991).

    Google Scholar 

  54. Mahuren, J.D. & Cobum, S.P. B-6 vitamers: cation exchange HPLC. Nutr. Biochem. 1, 659–663 (1990).

    Article  CAS  Google Scholar 

  55. Bell, R.R. & Haskell, B.E. Metabolism of vitamin B-6 in the l-strain mouse. Arch. Biochem. Biophys. 147, 588–601 (1971).

    Article  CAS  Google Scholar 

  56. Sasaki, T. Cell biology of tooth enamel formation. 1–204 (Karger, Basel, 1990).

Download references

Author information

Authors and Affiliations

  1. Department of Genetics and Molecular Medicine, Emory University School of Medicine, 1462 Clifton Rd. N.E., Atlanta, Georgia, 30322, USA

    Katrina G. Waymire, J. Michael Jaje & Grant R. MacGregor

  2. Fort Wayne State Developmental Center, 4900 St. Joe Rd., Fort Wayne State, Indiana, 46835, USA

    J. Dennis Mahuren & Stephen P. Coburn

  3. Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, 615 N. Wolfe St., Baltimore, Maryland, 21205, USA

    Tomás R. Guilarte

Authors
  1. Katrina G. Waymire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Dennis Mahuren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Michael Jaje
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomás R. Guilarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen P. Coburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Grant R. MacGregor
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waymire, K., Mahuren, J., Jaje, J. et al. Mice lacking tissue non–specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B–6. Nat Genet 11, 45–51 (1995). https://doi.org/10.1038/ng0995-45

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0995-45

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing