**7. Structure and function of mutant TNAP**

Mutation sites of TNAP proteins are classified by its domain structure [30]. Severe phenotypes are associated with the mutations that are located in the active site and its vicinity, the homodimer interface, the crown domain, and the calcium-binding domain. Mutations in the active site valley (the entry site of the substrate into the active site) resulted in less severe phenotypes [30]. Mutations in the other regions of the protein are inclined to show residual enzymatic activity and are, therefore, milder phenotypes.

Because most of the patients are compound heterozygotes, the residual activity and phenotype are determined by the interaction of two mutant proteins [55]. In some cases, especially in autosomal dominant cases, dominant negative mechanisms are suggested, in which cases the mutant proteins affect the function of the wild-type enzymes [48]. Those interactions have not been precisely elucidated and need to be explored in more detail in order to reveal the genotype–phenotype interrelationships and pathophysiology of HPP.
