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