title: Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations.
abstract: Hypophosphatasia is an inherited disorder caused by mutations in the bone alkaline phosphatase gene. We report here 11 new mutations responsible for hypophosphatasia. Four of them were deletions or insertions resulting in frameshift, two affected a donor splice site and five were missense mutations. Site-directed mutagenesis and transfection experiments of missense mutations showed that the mutations resulted in loss of most enzymatic activity, confirming the disease-causing role of these mutations. Analysis of the 3D model of tissue non-specific alkaline phosphatase showed that among the five missense mutations, one affected a residue in the crown domain and four affected residues located in the calcium-binding region. Alignment of the protein sequences of the calcium-binding region from 11 species showed that the four residues coordinating the calcium ion and the residues affected by the missense mutations described here are conserved in vertebrates. Together, our results confirm the functional role of the calcium site and suggest that its function is likely to be specific to vertebrates.
authors.affiliation: Equipe Structure-Fonction et Génétique, EA 2493, CHU Paris Ile de France Ouest, Université de Versailles-Saint Quentin en Yvelines, France. isabelle.brun-heath@cytogene.uvsq.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brun-Heath
authors.forename: Agnes
authors.initials: A
authors.lastname: Taillandier
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Serre
authors.forename: Etienne
authors.initials: E
authors.lastname: Mornet
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D005838:Genotype; D006801:Humans; D007014:Hypophosphatasia / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D017386:Sequence Homology, Amino Acid
chemical_list: D000469:Alkaline Phosphatase