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

D Fauvert, I Brun-Heath, AS Lia-Baldini, L Bellazi… - BMC medical …, 2009 - Springer
D Fauvert, I Brun-Heath, AS Lia-Baldini, L Bellazi, A Taillandier, JL Serre, P De Mazancourt…
BMC medical genetics, 2009Springer
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 …
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.
Springer