title: Childhood hypophosphatasia due to a de novo missense mutation in the tissue-nonspecific alkaline phosphatase gene.
abstract: Hypophosphatasia is an inherited disorder due to mutations in the bone alkaline phosphatase (ALPL) gene. We report here a patient with childhood hypophosphatasia diagnosed at 1.4 yr because of pectus excavatum, large anterior fontanel, rachitic skeletal changes, and low serum alkaline phosphatase. Sequencing of the ALPL gene produced evidence of two distinct missense mutations, E174K (c.571G>A), of maternal origin, and a de novo mutation, M45I (c.186G>C). The study of various microsatellite polymorphisms ruled out false paternity and therefore confirmed that M45I occurred de novo in the paternal germline or in the early development of the patient. Site-directed mutagenesis showed that M45I results in the absence of in vitro alkaline phosphatase activity, suggesting that the mutation is a severe allele. In conclusion, childhood hypophosphatasia in this patient is the result of compound heterozygosity for the moderate mutation E174K and a novel severe de novo mutation M45I.
authors.affiliation: Laboratoire SESEP, Batiment Fermat, Université de Versailles-Saint Quentin en Yvelines, 45 avenue des Etats-Unis, F-78035 Versailles, France.
authors.forename: A
authors.initials: A
authors.lastname: Taillandier
authors.forename: S-L
authors.initials: SL
authors.lastname: Sallinen
authors.forename: I
authors.initials: I
authors.lastname: Brun-Heath
authors.forename: P
authors.initials: P
authors.lastname: De Mazancourt
authors.forename: J-L
authors.initials: JL
authors.lastname: Serre
authors.forename: E
authors.initials: E
authors.lastname: Mornet
mesh_terms: D000293:Adolescent; D000469:Alkaline Phosphatase / Q000235:genetics*; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense
chemical_list: D000469:Alkaline Phosphatase