title: Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles.
abstract: 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.
authors.affiliation: Unité de Pathologie Cellulaire et Génétique EA2493, Université de Versailles-Saint Quentin en Yvelines, 78035 Versailles, France. lludland@aol.com
authors.forename: Delphine
authors.initials: D
authors.lastname: Fauvert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brun-Heath
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Lia-Baldini
authors.forename: Linda
authors.initials: L
authors.lastname: Bellazi
authors.forename: Agnès
authors.initials: A
authors.lastname: Taillandier
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Serre
authors.forename: Philippe
authors.initials: P
authors.lastname: de Mazancourt
authors.forename: Etienne
authors.initials: E
authors.lastname: Mornet
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; C548267:ALPL protein, human; D000469:Alkaline Phosphatase