Genetics of hypophosphatasia

Abstract

Hypophosphatasia (HPP) is a rare inherited disorder primarily affecting bone and dental mineralization. Although there is a continuum in the severity of the disease, clinical forms may be arbitrarily distinguished on the basis of age at onset and the presence or absence of bone symptoms: perinatal, infantile, juvenile, adult, prenatal benign, and odontological. Severe forms (perinatal and infantile) are autosomally recessively inherited while less severe forms may be autosomally recessively or dominantly inherited. Genetic counseling is complicated by the coexistence of the two modes of inheritance, the incomplete penetrance of the dominant forms, the markedly variable expression of the disease, including intra-familial expression, and the existence of a benign prenatal form that may sometimes be difficult to distinguish from the severe prenatal form. The disease is due to loss-of-function mutations in the Alkaline Phosphatase-Liver (ALPL) gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). The great variety of missence mutations and the dominant negative effect of some mutations largely explain the clinical heterogeneity. Directed mutagenesis studies allowed further elucidation of the cellular pathophysiology of HPP, classification of the alleles in terms of their severity and dominant negative effect, and molecular explanations of the dominant inheritance mode. Genetics significantly contributed to show that there are in fact two HPPs, rare, severe and recessive HPP, and mild recessive or mild dominant HPP, which is markedly more frequent and probably under-diagnosed. The prevalence of the severe forms of HPP has been estimated to be 1/300,000 in France and Northern Europe while the prevalence of the moderate forms of HPP may reach 1/6,370.