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Gene Review

ALPL  -  alkaline phosphatase, liver/bone/kidney

Homo sapiens

Synonyms: AP-TNAP, APTNAP, Alkaline phosphatase liver/bone/kidney isozyme, Alkaline phosphatase, tissue-nonspecific isozyme, HOPS, ...
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Disease relevance of ALPL

  • A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites [1].
  • CONCLUSIONS: These results suggest that variation in TNSALP may be an important determinant of age-related bone loss in humans and that the phosphate metabolism pathway may provide a novel target for the prevention and treatment of osteoporosis [2].
  • Histochemically, loss of alkaline phosphatase activity (ALPL, liver/bone/kidney type, EC was another frequent, specific finding in meningiomas with signs of dedifferentiation [3].
  • Hypophosphatasia, a heritable disease characterized by deficient activity of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP), results in rickets and osteomalacia [4].
  • Hypophosphatasia is a rare metabolic bone disease characterized biochemically by deficient enzymatic activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) [5].

High impact information on ALPL

  • Hypophosphatasia features selective deficiency of activity of the tissue-nonspecific (liver/bone/kidney) alkaline phosphatase (ALP) isoenzyme (TNSALP); placental and intestinal ALP isoenzyme (PALP and IALP, respectively) activity is not reduced [6].
  • Three phosphocompounds (phosphoethanolamine [PEA], inorganic pyrophosphate [PPi], and pyridoxal 5'-phosphate [PLP]) accumulate endogenously and appear, therefore, to be natural substrates for TNSALP [6].
  • Our findings help to explain the general absence of symptoms of vitamin B6 excess or deficiency in hypophosphatasia, and provide evidence that TNSALP acts as an ectoenzyme to regulate extracellular rather than intracellular concentrations of PLP (the cofactor form of vitamin B6) and perhaps other phosphate compounds [7].
  • Previously, we demonstrated in one inbred infant that an identical missense mutation in both alleles of the gene encoding TNSALP caused lethal disease [8].
  • Each of the eight TNSALP alleles from these four individuals contains a different point mutation that causes an amino acid substitution [8].

Biological context of ALPL

  • The gene coding for the liver/bone/kidney isozyme of alkaline phosphatase, ALPL, has been mapped to human chromosome 1 using a monoclonal antibody TRA-2-54/2J and electrophoretic analysis to distinguish between the human and rodent isozymes in human/rodent somatic cell hybrids [9].
  • Comparative histochemical and molecular cytogenetic studies point to the alkaline phosphatase gene (ALPL, liver-bone-kidney type) located on 1p36.1-->p34 as a candidate tumor suppressor gene [10].
  • Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from a tissue-nonspecific ALP (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization [2].
  • To analyze the protein translated from the TNSALP gene associated with BMD, we constructed a TNSALP cDNA expression plasmid [2].
  • Primers and conditions were established for all TNSALP coding exons (2-12) and adjacent splice sites so that the amplicons incorporated a GC clamp on one end [11].

Anatomical context of ALPL

  • Bovine embryonic stem (bES) cell lines reported to date vary in morphology and marker expression, such as alkaline phosphatase (ALPL), stage-specific embryonic antigen 4 (SSEA4), and octamer-binding transcription factor-4 (OCT4), that normally are associated with the undifferentiated, pluripotent state [12].
  • Expression of the 787T>C TNSALP gene using COS-1 cells showed that the protein translated from 787T>C had ALP-specific activity similar to that of 787T [2].
  • The initial site of mineralization (primary mineralization) normally occurs within the lumen of TNSALP-rich matrix vesicles (MVs) of growth cartilage, bone, and dentin [4].
  • An 8-month-old girl who seemed certain to die from the infantile form of hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets [13].

Associations of ALPL with chemical compounds


Other interactions of ALPL

  • Using polymorphisms at other 1p loci (ALPL, the gene for alkaline phosphatase, RH and D1S57), we have been able to map APNH telomeric to D1S57 and close to RH and ALPL by genetic linkage [18].
  • Although identification of TNSALP gene defects in hypophosphatasia establishes a role of ALP in skeletal mineralization, the precise function remains unclear [4].
  • Median enzyme concentration were increased in 'poor' compared to 'good' prognosis patients: start IAP 3.2 versus 2.2 U/g creat (NS), start NAG 48.6 versus 13.7 (P < 0.01), start TNAP 3.5 versus 0.9 (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)[19]
  • Characterization of Missense Mutations and Large Deletions in the ALPL Gene by Sequencing and Quantitative Multiplex PCR of Short Fragments [20].
  • Using a candidate gene approach, we investigated possible linkage of EARR associated with orthodontic treatment with the TNSALP, TNFalpha, and TNFRSF11A gene loci [21].

Analytical, diagnostic and therapeutic context of ALPL


  1. A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Greenberg, C.R., Taylor, C.L., Haworth, J.C., Seargeant, L.E., Philipps, S., Triggs-Raine, B., Chodirker, B.N. Genomics (1993) [Pubmed]
  2. Functional analysis of the single nucleotide polymorphism (787T>C) in the tissue-nonspecific alkaline phosphatase gene associated with BMD. Goseki-Sone, M., Sogabe, N., Fukushi-Irie, M., Mizoi, L., Orimo, H., Suzuki, T., Nakamura, H., Orimo, H., Hosoi, T. J. Bone Miner. Res. (2005) [Pubmed]
  3. Loss of alkaline phosphatase activity in meningiomas: a rapid histochemical technique indicating progression-associated deletion of a putative tumor suppressor gene on the distal part of the short arm of chromosome 1. Niedermayer, I., Feiden, W., Henn, W., Steilen-Gimbel, H., Steudel, W.I., Zang, K.D. J. Neuropathol. Exp. Neurol. (1997) [Pubmed]
  4. Matrix vesicles in osteomalacic hypophosphatasia bone contain apatite-like mineral crystals. Anderson, H.C., Hsu, H.H., Morris, D.C., Fedde, K.N., Whyte, M.P. Am. J. Pathol. (1997) [Pubmed]
  5. Hypophosphatasia: levels of bone alkaline phosphatase immunoreactivity in serum reflect disease severity. Whyte, M.P., Walkenhorst, D.A., Fedde, K.N., Henthorn, P.S., Hill, C.S. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  6. Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate. Substrate accumulation in carriers of hypophosphatasia corrects during pregnancy. Whyte, M.P., Landt, M., Ryan, L.M., Mulivor, R.A., Henthorn, P.S., Fedde, K.N., Mahuren, J.D., Coburn, S.P. J. Clin. Invest. (1995) [Pubmed]
  7. Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase. Whyte, M.P., Mahuren, J.D., Fedde, K.N., Cole, F.S., McCabe, E.R., Coburn, S.P. J. Clin. Invest. (1988) [Pubmed]
  8. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Henthorn, P.S., Raducha, M., Fedde, K.N., Lafferty, M.A., Whyte, M.P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  9. Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1. Swallow, D.M., Povey, S., Parkar, M., Andrews, P.W., Harris, H., Pym, B., Goodfellow, P. Ann. Hum. Genet. (1986) [Pubmed]
  10. Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases. Zang, K.D. Cytogenet. Cell Genet. (2001) [Pubmed]
  11. Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mumm, S., Jones, J., Finnegan, P., Henthorn, P.S., Podgornik, M.N., Whyte, M.P. Mol. Genet. Metab. (2002) [Pubmed]
  12. Bovine embryonic stem cells. Roach, M., Wang, L., Yang, X., Tian, X.C. Meth. Enzymol. (2006) [Pubmed]
  13. Marrow cell transplantation for infantile hypophosphatasia. Whyte, M.P., Kurtzberg, J., McAlister, W.H., Mumm, S., Podgornik, M.N., Coburn, S.P., Ryan, L.M., Miller, C.R., Gottesman, G.S., Smith, A.K., Douville, J., Waters-Pick, B., Armstrong, R.D., Martin, P.L. J. Bone Miner. Res. (2003) [Pubmed]
  14. Induction of heat labile alkaline phosphatase by butyrate in differentiating endometrial cells. Fleming, H., Begley, M., Campi, T., Condon, R., Dobyns, K., McDonagh, J., Wallace, S. J. Cell. Biochem. (1995) [Pubmed]
  15. Xanthohumol, a novel anti-HIV-1 agent purified from Hops Humulus lupulus. Wang, Q., Ding, Z.H., Liu, J.K., Zheng, Y.T. Antiviral Res. (2004) [Pubmed]
  16. Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). Overk, C.R., Yao, P., Chadwick, L.R., Nikolic, D., Sun, Y., Cuendet, M.A., Deng, Y., Hedayat, A.S., Pauli, G.F., Farnsworth, N.R., van Breemen, R.B., Bolton, J.L. J. Agric. Food Chem. (2005) [Pubmed]
  17. In vitro and ex vivo cyclooxygenase inhibition by a hops extract. Lemay, M., Murray, M.A., Davies, A., Roh-Schmidt, H., Randolph, R.K. Asia Pacific journal of clinical nutrition. (2004) [Pubmed]
  18. The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1. Dudley, C.R., Giuffra, L.A., Tippett, P., Kidd, K.K., Reeders, S.T. Hum. Genet. (1990) [Pubmed]
  19. Urinary enzymes in acute renal failure. Chew, S.L., Lins, R.L., Daelemans, R., Nuyts, G.D., De Broe, M.E. Nephrol. Dial. Transplant. (1993) [Pubmed]
  20. Characterization of Missense Mutations and Large Deletions in the ALPL Gene by Sequencing and Quantitative Multiplex PCR of Short Fragments. Spentchian, M., Brun-Heath, I., Taillandier, A., Fauvert, D., Serre, J.L., Simon-Bouy, B., Carvalho, F., Grochova, I., Mehta, S.G., Müller, G., Oberstein, S.L., Ogur, G., Sharif, S., Mornet, E. Genet. Test. (2006) [Pubmed]
  21. Genetic predisposition to external apical root resorption in orthodontic patients: linkage of chromosome-18 marker. Al-Qawasmi, R.A., Hartsfield, J.K., Everett, E.T., Flury, L., Liu, L., Foroud, T.M., Macri, J.V., Roberts, W.E. J. Dent. Res. (2003) [Pubmed]
  22. Correlations of genotype and phenotype in hypophosphatasia. Zurutuza, L., Muller, F., Gibrat, J.F., Taillandier, A., Simon-Bouy, B., Serre, J.L., Mornet, E. Hum. Mol. Genet. (1999) [Pubmed]
  23. Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene. Mornet, E. Hum. Mutat. (2000) [Pubmed]
  24. PCR detection of a BclI RFLP in the human ALPL gene. Okuyama, T., Matsuo, N., Kudoh, J., Shimizu, N. Nucleic Acids Res. (1991) [Pubmed]
  25. Phosphate depletion enhances bone morphogenetic protein-4 gene expression in a cultured mouse marrow stromal cell line ST2. Goseki-Sone, M., Yamada, A., Hamatani, R., Mizoi, L., Iimura, T., Ezawa, I. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
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