Hypophosphatasia: The mutations in the tissue-nonspecific alkaline phosphatase gene

Hypophosphatasia is an inborn error of metabolism caused by a deficiency of liver-, bone- or kidney-type alkaline phosphatase due to mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Most of the 65 distinc t mutations described to date are missense mutations, a result which must b e correlated with the great variability of clinical expression ranging from stillbirth without mineralized bone to pathologic fractures developing onl y late in adulthood. Correlations of genotype and phenotype have been estab lished on the basis of clinical data exhibited by the patients, transfectio n studies, computer-assisted modeling, and examination of biochemical prope rties of ALP in cultured fibroblasts of patients. Screening for mutations i n the TNSALP gene allows genetic counseling and prenatal diagnosis of the d isease in families with severe forms of hypophosphatasia, and screening may also be helpful in confirming diagnosis of hypophosphatasia when biochemic al and clinical data are not clear. Screening is also the necessary first s tep in further studies to elucidate dominant transmission of the disease an d of liver-, bone- and kidney-type alkaline phosphatase activity mechanism. Hum Mutat 15:309-315, 2000. (C) 2000 Wiley-Liss, Inc.