Molecular Genetics of Hypophosphatasia

Abstract

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).

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Further Reading

Mornet E and Nunes ME (2011) Hypophosphatasia (Review) GeneReviews, PMID 20301329, http://www.ncbi.nlm.nih.gov/books/NBK1150/

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.

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Mornet, Etienne(Dec 2012) Molecular Genetics of Hypophosphatasia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024292]