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


CONCLUSIONS
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.
Fauvert
Delphine
D
Unité de Pathologie Cellulaire et Génétique EA2493, Université de Versailles-Saint Quentin en Yvelines, 78035 Versailles, France. lludland@aol.com
Brun-Heath
Isabelle
I
Lia-Baldini
Anne-Sophie
AS
Bellazi
Linda
L
Taillandier
Agnès
A
Serre
Jean-Louis
JL
de Mazancourt
Philippe
P
Mornet
Etienne
E
D000328:Adult; D000469:Alkaline Phosphatase / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005799:Genes, Dominant; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics*; D007223:Infant; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary
D002352:Carrier Proteins; C548267:ALPL protein, human; D000469:Alkaline Phosphatase