Molecular Genetics of Hypophosphatasia


Hypophosphatasia (HPP) is a rare inherited disorder affecting bone and dental mineralisation. The disease is due to loss‐of‐function mutations in the ALPL gene that encodes the tissue‐nonspecific alkaline phosphatase (TNSALP). Genetic aspects of HPP, and their molecular bases, are particularly exciting, due to the inheritance that may be recessive or dominant, the extremely variable clinical and allelic heterogeneity, and the puzzling and inconstant prenatal evolution. During the past 15 years, a great effort has been conducted by various groups to evaluate the effect of alkaline phosphatase liver type gene (ALPL) mutations and to decipher genotype–phenotype relationships. A very large part of the clinical heterogeneity is due to the great variety of missense mutations that allow variable enzymatic activity of TNSALP, as shown by site‐directed mutagenesis experiments. A residual part, that remains to be studied, could be due to modifier genes, epigenetic and environmental factors.

Key Concepts:

  • The high clinical variability observed in HPP for a large part result from the very high allelic variability of the ALPL gene.

  • Missense mutations allow possible residual alkaline phosphatase activity, explaining moderate alleles responsible for mild phenotypes.

  • Alkaline phosphatase is an allosteric enzyme active in a dimeric form, and the formation of mutant/wild‐type dimers explains the dominant inheritance often observed in moderate hypophosphatasia.

  • Site‐directed mutagenesis experiments and 3D‐modelling show a good correlation of genotype and phenotype.

  • However, recent deciphering of bone mineralisation suggests that other genes, and perhaps environmental and/or epigenetic factors, could play a role in modulating the hypophosphatasia phenotype.

Keywords: hypophosphatasia; mutations; ALPL; genotype–phenotype correlation; tissue‐nonspecific alkaline phosphatase

Figure 1.

3D modelling of TNSALP showing the functional domains of the protein. The two molecules forming the functional homodimer are shown in yellow and magenta, respectively. The catalytic site is displayed with green spheres. The N‐terminal arm (shown in grey) is essential for stability and allosteric properties of the enzyme (Hoylaerts et al., ). The crown domain (orange ribbon) is a key factor of uncompetitive inhibition (Kozlenkov et al., ), heat‐stability (Bossi et al., ) and allosteric behaviour (Hoylaerts et al., ). The crown domain may be also involved in the binding of TNAP to collagen (Hoylaerts and Millan, ; Bossi et al., ), corroborating previous studies that suggested this property of TNAP (Vittur et al., ; Wu et al., ). The homodimer interface is also considered as a functional domain because it is indispensable for allostery and because alkaline phosphatases are active only in dimeric form. The exact role of the calcium‐binding site (shown in cyan, with the Ca2+ atom shown in blue) remains to be elucidated.

Figure 2.

Attempt to explain recessive and dominant inheritance of HPP at the cell level. In recessive inheritance, the mutated monomer fails to reach the cell membrane, is accumulated in the cis‐golgi and is subsequently degraded in the proteasome (up). The normal allele produces 50% of the wild type (WT) cell activity. Alternatively, the mutated monomer may be not degraded and may consequently dimerise with the WT monomer, allowing the normal monomer to produce activity (down). In dominant inheritance, the mutated monomer may inhibit the WT monomer activity (up) or the dimer may be sequestrated in the cytoplasm, possibly resulting in obvious, but useless in vitro activity (down).



Beck C, Morbach H, Richl P, Stenzel M and Girschick HJ (2009) How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases? Rheumatology International 29: 229–238.

Beck C, Morbach H, Wirth C, Beer M and Girschick HJ (2011) Whole‐body MRI in the childhood form of hypophosphatasia. Rheumatology International 31: 1315–1320.

Bossi M, Hoylaerts MF and Millan JL (1993) Modifications in a flexible surface loop modulate the isozyme‐specific properties of mammalian alkaline phosphatases. Journal of Biological Chemistry 268: 25409–25416.

Fauvert D, Brun‐Heath I, Lia‐Baldini AS et al. (2009) Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Medical Genetics 10: 51.

Fraser D (1957) Hypophosphatasia. American Journal of Medicine 22: 730–746.

Girschick HJ, Mornet E, Beer M, Warmuth‐Metz M and Schneider P (2007) Chronic multifocal non‐bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatrics 7: 3.

Harmey D, Hessle L, Narisawa S et al. (2004) Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. American Journal of Pathology 164: 1199–1209.

Herasse M, Spentchian M, Taillandier A et al. (2003) Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non‐specific alkaline phosphatase gene. Journal of Medical Genetics 40: 605–609.

Hessle L, Johnson KA, Anderson HC et al. (2002) Tissue‐nonspecific alkaline phosphatase and plasma cell membrane glycoprotein‐1 are central antagonistic regulators of bone mineralization. Proceedings of the National Academy of Sciences of the USA 99: 9445–9449.

Hoylaerts MF and Millan JL (1991) Site‐directed mutagenesis and epitope‐mapped monoclonal antibodies define a catalytically important conformational difference between human placental and germ cell alkaline phosphatase. European Journal of Biochemistry 202: 605–616.

Hoylaerts MF, Ding L, Narisawa S, Van Kerckhoven S and Millan JL (2006) Mammalian alkaline phosphatase catalysis requires active site structure stabilization via the N‐terminal amino acid microenvironment. Biochemistry 45: 9756–9766.

Hoylaerts MF, Manes T and Millan JL (1997) Mammalian alkaline phosphatases are allosteric enzymes. Journal of Biological Chemistry 272: 22781–22787.

Ishida Y, Komaru K, Ito M et al. (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 (Tokyo) 134: 63–70.

Ishida Y, Komaru K and Oda K (2011) Molecular characterization of tissue‐nonspecific alkaline phosphatase with an Ala to Thr substitution at position 116 associated with dominantly inherited hypophosphatasia. Biochimica et Biophysica Acta 1812: 326–332.

Ito M, Amizuka N, Ozawa H and Oda K (2002) Retention at the cis‐Golgi and delayed degradation of tissue‐non‐specific alkaline phosphatase with an Asn153→Asp substitution, a cause of perinatal hypophosphatasia. Biochemical Journal 361: 473–480.

Kozlenkov A, Le Du MH, Cuniasse P et al. (2004) Residues determining the binding specificity of uncompetitive inhibitors to tissue‐nonspecific alkaline phosphatase. Journal of Bone and Mineral Research 19: 1862–1872.

Le Du MH, Stigbrand T, Taussig MJ, Menez A and Stura EA (2001) Crystal structure of alkaline phosphatase from human placenta at 1.8 A resolution. Implication for a substrate specificity. Journal of Biological Chemistry 276: 9158–9165.

Lia‐Baldini AS, Brun‐Heath I, Carrion C et al. (2008) A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild‐type protein. Human Genetics 123: 429–432.

Lia‐Baldini AS, Muller F, Taillandier A et al. (2001) A molecular approach to dominance in hypophosphatasia. Human Genetics 109: 99–108.

Mentrup B, Marschall C, Barvencik F et al. (2011) Functional characterization of a novel mutation localized in the start codon of the tissue‐nonspecific alkaline phosphatase gene. Bone 48: 1401–1408.

Michigami T, Uchihashi T, Suzuki A et al. (2005) Common mutations F310L and T1559del in the tissue‐nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia. European Journal of Pediatrics 164: 277–282.

Millan J (2006) Mammalian Alkaline Phosphatases: From Biology to Applications in Medicine and Biotechnology. Weinheim: Wiley‐VCH Verlag GmbH.

Moore CA, Curry CJ, Henthorn PS et al. (1999) Mild autosomal dominant hypophosphatasia: in utero presentation in two families. American Journal of Medical Genetics 86: 410–415.

Mornet E (2007) Hypophosphatasia. Orphanet Journal of Rare Diseases 2: 40.

Mornet E (2008) Hypophosphatasia. Best Practice and Research Clinical Rheumatology 22: 113–127.

Mornet E, Stura E, Lia‐Baldini AS et al. (2001) Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. Journal of Biological Chemistry 276: 31171–31178.

Mornet E, Yvard A, Taillandier A, Fauvert D and Simon‐Bouy B (2011) A molecular‐based estimation of the prevalence of hypophosphatasia in the European population. Annals of Human Genetics 75: 439–445.

Muller HL, Yamazaki M, Michigami T et al. (2000) Asp361Val mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild‐type enzyme. Journal of Clinical Endocrinology and Metabolism 85: 743–747.

Numa N, Ishida Y, Nasu M et al. (2008) Molecular basis of perinatal hypophosphatasia with tissue‐nonspecific alkaline phosphatase bearing a conservative replacement of valine by alanine at position 406. Structural importance of the crown domain. Federation of European Biochemical Societies Journal 275: 2727–2737.

Pauli RM, Modaff P, Sipes SL and Whyte MP (1999) Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken. American Journal of Medical Genetics 86: 434–438.

Petkovic Ramadza D, Stipoljev F, Sarnavka V et al. (2009) Hypophosphatasia: phenotypic variability and possible Croatian origin of the c.1402g>A mutation of TNSALP gene. Collegium Antropologicum 33: 1255–1258.

Rathbun JC (1948) Hypophosphatasia; a new developmental anomaly. American Journal of Diseases of Children 75: 822–831.

Reibel A, Maniere MC, Clauss F et al. (2009) Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. Orphanet Journal of Rare Diseases 4: 6.

Rodrigues TL, Foster BL, Silverio KG et al. (2011) Correction of hypophosphatasia (hpp) associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells. Journal of Periodontology 83: 653–663.

Sinico M, Levaillant JM, Vergnaud A et al. (2007) Specific osseous spurs in a lethal form of hypophosphatasia correlated with 3D prenatal ultrasonographic images. Prenatal Diagnosis 27: 222–227.

Spentchian M, Brun‐Heath I, Taillandier A et al. (2006) Characterization of missense mutations and large deletions in the ALPL gene by sequencing and quantitative multiplex PCR of short fragments. Genetic Testing 10: 252–257.

Sugano H, Matsumoto T, Miyake K et al. (2012) Successful gene therapy in utero for lethal murine hypophosphatasia. Human Gene Therapy 23: 399–406.

Taillandier A, Sallinen SL, Brun‐Heath I et al. (2005) Childhood hypophosphatasia due to a de novo missense mutation in the tissue‐nonspecific alkaline phosphatase gene. Journal of Clinical Endocrinology and Metabolism 90: 2436–2439.

Vittur F, Stagni N, Moro L and De Bernard B (1984) Alkaline phosphatase binds to collagen; a hypothesis on the mechanism of extravesicular mineralization in epiphyseal cartilage. Experientia 40: 836–837.

Watanabe A, Satoh S, Fujita A et al. (2012) Perinatal (lethal) type of hypophosphatasia resulting from paternal isodisomy of chromosome 1. In: 6th Alkaline Phosphatase and Hypophosphatasia Symposium, 16–19 May 2012, Huningue, France.

Weiss MJ, Ray K, Henthorn PS et al. (1988) Structure of the human liver/bone/kidney alkaline phosphatase gene. Journal of Biological Chemistry 263: 12002–12010.

Wenkert D, Mcalister WH, Coburn SP et al. (2011) Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). Journal of Bone and Mineral Research 26: 2389–2398.

Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocrine Reviews 15: 439–461.

Whyte MP (2010) Physiological role of alkaline phosphatase explored in hypophosphatasia. Annals of the New York Academy of Sciences 1192: 190–200.

Whyte MP, Essmyer K, Geimer M and Mumm S (2006) Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry. Journal of Pediatrics 148: 753–758.

Whyte MP, Greenberg CR, Salman NJ et al. (2012) Enzyme‐replacement therapy in life‐threatening hypophosphatasia. New England Journal of Medicine 366: 904–913.

Whyte MP, Wenkert D, Mcalister WH et al. (2009) Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia. Journal of Bone and Mineral Research 24: 1493–1505.

Wu LN, Genge BR, Lloyd GC and Wuthier RE (1991) Collagen‐binding proteins in collagenase‐released matrix vesicles from cartilage. Interaction between matrix vesicle proteins and different types of collagen. Journal of Biological Chemistry 266: 1195–1203.

Yadav MC, Simao AM, Narisawa S et al. (2011) Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. Journal of Bone and Mineral Research 26: 286–297.

Zhang H, Ke YH, Wang C et al. (2012) Identification of the mutations in the tissue‐nonspecific alkaline phosphatase gene in two Chinese families with hypophosphatasia. Archives of Medical Research 43: 21–30.

Further Reading

Mornet E and Nunes ME (2011) Hypophosphatasia (Review) GeneReviews, PMID 20301329,

Orimo H (2010) The mechanism of mineralization and the role of alkaline phosphatase in health and disease (Review). Journal of Nippon Medical School 77(1): 4–12.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mornet, Etienne(Dec 2012) Molecular Genetics of Hypophosphatasia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024292]