IDENTIFICATION OF 15 NOVEL MUTATIONS IN THE TISSUE-NONSPECIFIC ALKALINE-PHOSPHATASE (TNSALP) GENE IN EUROPEAN PATIENTS WITH SEVERE HYPOPHOSPHATASIA

Hypophosphatasia is an inherited disorder characterised by defective b one mineralisation and deficiency of serum and tissue liver/bone/kidne y alkaline phosphatase (L/B/K ALP) activity. We report the characteris ation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutatio ns in a series of 13 European families affected by perinatal, infantil e or childhood hypophosphatasia. Eighteen distinct mutations were foun d, only three of which had been reported previously in North American and Japanese populations. Most of the 15 new mutations were missense m utations, but we also found two mutations affecting donor splice sites and a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affects the final maturation of the protein. Despite extensive sequencing of the gene and its promotor reg ion, only one mutation was identified in two cases, one of which was c ompatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the TNSALP gene. In 12 of the 13 te sted families, genetic diagnosis was possible by characterisation of t he mutations or by use of polymorphisms as genetic markers. Hypophosph atasia diagnosis was assigned in two families where clinical, laborato ry and radiographic data were unclear and prenatal diagnosis was perfo rmed in one case. The results also show that severe hypophosphatasia i s due to a very large spectrum of mutations in European populations wi th no prevalent mutation and that genetic diagnosis of the disease mus t be performed by extensive analysis of the gene.