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Background  Mild hypophosphatasia (HPP) phenotype may result from  ALPL  gene mutations exhibiting residual alkaline phosphatase activity or from severe heterozygous mutations exhibiting a dominant negative effect. In order to determine the cause of our failure to detect a second mutation by sequencing in patients with mild HPP and carrying on a single heterozygous mutation, we tested the possible dominant effect of 35 mutations carried by these patients.    Methods  We tested the mutations by site-directed mutagenesis. We also genotyped 8 exonic and intronic  ALPL  gene polymorphisms in the patients and in a control group in order to detect the possible existence of a recurrent intronic mild mutation.    Results  We found that most of the tested mutations exhibit a dominant negative effect that may account for the mild HPP phenotype, and that for at least some of the patients, a second mutation in linkage disequilibrium with a particular haplotype could not be ruled out.    Conclusion  Mild HPP results in part from compound heterozygosity for severe and moderate mutations, but also in a large part from heterozygous mutations with a dominant negative effect.

bmc medical genetics

Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles