ALPL

ALPL
Identifiers
AliasesALPL, AP-TNAP, APTNAP, HOPS, TNAP, TNSALP, alkaline phosphatase, liver/bone/kidney, TNALP, alkaline phosphatase, biomineralization associated
External IDsMGI: 87983 HomoloGene: 37314 GeneCards: ALPL
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1p36.12Start21,509,372 bp[1]
End21,578,412 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

249

11647

Ensembl

ENSG00000162551

ENSMUSG00000028766

UniProt

P05186

P09242

RefSeq (mRNA)

NM_000478
NM_001127501
NM_001177520

NM_001287172
NM_001287176
NM_007431

RefSeq (protein)

NP_000469
NP_001120973
NP_001170991

NP_001274101
NP_031457

Location (UCSC)Chr 1: 21.51 – 21.58 MbChr 4: 137.74 – 137.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene.[5][6]

Function

There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue-nonspecific). The first three are located together on chromosome 2, whereas the tissue-nonspecific form is located on chromosome 1. The product of this gene is a membrane-bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. The exact physiological function of the alkaline phosphatases is not known. A proposed function of this form of the enzyme is matrix mineralization. However, mice that lack a functional form of this enzyme show normal skeletal development.[7]

Clinical significance

This enzyme has been linked directly to a disorder known as hypophosphatasia, a disorder that is characterized by hypercalcemia and includes skeletal defects. The character of this disorder can vary, however, depending on the specific mutation, since this determines age of onset and severity of symptoms.

The severity of symptoms ranges from premature loss of deciduous teeth with no bone abnormalities to stillbirth[8] depending upon which amino acid[9][10]

is changed in the ALPL gene. Mutations in the ALPL gene lead to varying low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP) resulting in hypophosphatasia (HPP).[11] There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait,[8] the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth.[11] ALPL gene mutation leads to insufficient TNSALP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate[11] to indirectly cause elevated calcium levels in the body and lack of bone calcification.

The mutation E174K, where a glycine is converted to an alanine amino acid at the 571st position of its respective polypeptide chain, is a result of an ancestral mutation that occurred in Caucasians and shows a mild form of HPP.[8]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162551 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028766 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Weiss MJ, Henthorn PS, Lafferty MA, Slaughter C, Raducha M, Harris H (October 1986). "Isolation and characterization of a cDNA encoding a human liver/bone/kidney-type alkaline phosphatase". Proceedings of the National Academy of Sciences of the United States of America. 83 (19): 7182–6. doi:10.1073/pnas.83.19.7182. PMC 386679. PMID 3532105.
  6. ↑ Swallow DM, Povey S, Parkar M, Andrews PW, Harris H, Pym B, Goodfellow P (July 1986). "Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1". Annals of Human Genetics. 50 (Pt 3): 229–35. doi:10.1111/j.1469-1809.1986.tb01043.x. PMID 3446011.
  7. ↑ "Entrez Gene: ALPL alkaline phosphatase, liver/bone/kidney".
  8. 1 2 3 Hérasse M, Spentchian M, Taillandier A, Mornet E (October 2002). "Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients". European Journal of Human Genetics. 10 (10): 666–8. doi:10.1038/sj.ejhg.5200857. PMID 12357339.
  9. ↑ Nasu M, Ito M, Ishida Y, Numa N, Komaru K, Nomura S, Oda K (December 2006). "Aberrant interchain disulfide bridge of tissue-nonspecific alkaline phosphatase with an Arg433→Cys substitution associated with severe hypophosphatasia". The FEBS Journal. 273 (24): 5612–24. doi:10.1093/oxfordjournals.jbchem.a022032. PMID 17212778.
  10. ↑ Ishida Y, Komaru K, Ito M, Amaya Y, Kohno S, Oda K (July 2003). "Tissue-nonspecific alkaline phosphatase with an Asp(289)→Val mutation fails to reach the cell surface and undergoes proteasome-mediated degradation". Journal of Biochemistry. 134 (1): 63–70. doi:10.1093/jb/mvg114. PMID 12944372.
  11. 1 2 3 Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millán JL, MacGregor GR, Whyte MP (December 1999). "Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia". Journal of Bone and Mineral Research. 14 (12): 2015–26. doi:10.1359/jbmr.1999.14.12.2015. PMC 3049802. PMID 10620060.

Further reading

  • Mornet E (2000). "Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene". Human Mutation. 15 (4): 309–15. doi:10.1002/(SICI)1098-1004(200004)15:4<309::AID-HUMU2>3.0.CO;2-C. PMID 10737975.
  • Khandwala HM, Mumm S, Whyte MP (2007). "Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood". Endocrine Practice. 12 (6): 676–81. doi:10.4158/ep.12.6.676. PMID 17229666.
  • Nye KE, Riley GA, Pinching AJ (July 1992). "The defect seen in the phosphatidylinositol hydrolysis pathway in HIV-infected lymphocytes and lymphoblastoid cells is due to inhibition of the inositol 1,4,5-trisphosphate 1,3,4,5-tetrakisphosphate 5-phosphomonoesterase". Clinical and Experimental Immunology. 89 (1): 89–93. doi:10.1111/j.1365-2249.1992.tb06883.x. PMC 1554388. PMID 1321014.
  • Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP (October 1992). "Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia". Proceedings of the National Academy of Sciences of the United States of America. 89 (20): 9924–8. doi:10.1073/pnas.89.20.9924. PMC 50246. PMID 1409720.
  • Nishihara Y, Hayashi Y, Adachi T, Koyama I, Stigbrand T, Hirano K (December 1992). "Chemical nature of intestinal-type alkaline phosphatase in human kidney". Clinical Chemistry. 38 (12): 2539–42. PMID 1458595.
  • Fedde KN, Whyte MP (November 1990). "Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5'-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study". American Journal of Human Genetics. 47 (5): 767–75. PMC 1683690. PMID 2220817.
  • Kishi F, Matsuura S, Kajii T (March 1989). "Nucleotide sequence of the human liver-type alkaline phosphatase cDNA". Nucleic Acids Research. 17 (5): 2129. doi:10.1093/nar/17.5.2129. PMC 317555. PMID 2928120.
  • Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H (August 1988). "Structure of the human liver/bone/kidney alkaline phosphatase gene". The Journal of Biological Chemistry. 263 (24): 12002–10. PMID 3165380.
  • Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H (October 1988). "A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia". Proceedings of the National Academy of Sciences of the United States of America. 85 (20): 7666–9. doi:10.1073/pnas.85.20.7666. PMC 282253. PMID 3174660.
  • Smith M, Weiss MJ, Griffin CA, Murray JC, Buetow KH, Emanuel BS, Henthorn PS, Harris H (February 1988). "Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1p36.1-p34". Genomics. 2 (2): 139–43. doi:10.1016/0888-7543(88)90095-X. PMID 3410475.
  • Garattini E, Hua JC, Pan YC, Udenfriend S (March 1986). "Human liver alkaline phosphatase, purification and partial sequencing: homology with the placental isozyme". Archives of Biochemistry and Biophysics. 245 (2): 331–7. doi:10.1016/0003-9861(86)90223-7. PMID 3954357.
  • Goldstein DJ, Blasco L, Harris H (July 1980). "Placental alkaline phosphatase in nonmalignant human cervix". Proceedings of the National Academy of Sciences of the United States of America. 77 (7): 4226–8. doi:10.1073/pnas.77.7.4226. PMC 349804. PMID 6933471.
  • Sato N, Takahashi Y, Asano S (February 1994). "Preferential usage of the bone-type leader sequence for the transcripts of liver/bone/kidney-type alkaline phosphatase gene in neutrophilic granulocytes". Blood. 83 (4): 1093–101. PMID 7509208.
  • Orimo H, Hayashi Z, Watanabe A, Hirayama T, Hirayama T, Shimada T (September 1994). "Novel missense and frameshift mutations in the tissue-nonspecific alkaline phosphatase gene in a Japanese patient with hypophosphatasia". Human Molecular Genetics. 3 (9): 1683–4. doi:10.1093/hmg/3.9.1683. PMID 7833929.
  • Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN (July 1993). "A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites". Genomics. 17 (1): 215–7. doi:10.1006/geno.1993.1305. PMID 8406453.
  • Ozono K, Yamagata M, Michigami T, Nakajima S, Sakai N, Cai G, Satomura K, Yasui N, Okada S, Nakayama M (December 1996). "Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia". The Journal of Clinical Endocrinology and Metabolism. 81 (12): 4458–61. doi:10.1210/jc.81.12.4458. PMID 8954059.
  • Orimo H, Goseki-Sone M, Sato S, Shimada T (June 1997). "Detection of deletion 1154-1156 hypophosphatasia mutation using TNSALP exon amplification". Genomics. 42 (2): 364–6. doi:10.1006/geno.1997.4733. PMID 9192863.
  • Sugimoto N, Iwamoto S, Hoshino Y, Kajii E (1998). "A novel missense mutation of the tissue-nonspecific alkaline phosphatase gene detected in a patient with hypophosphatasia". Journal of Human Genetics. 43 (3): 160–4. doi:10.1007/s100380050061. PMID 9747027.
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