title: A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria.
abstract: Phenylketonuria (PKU) is an autosomal recessive disease due to deficiency of a hepatic enzyme, phenylalanine hydroxylase (PAH). The absence of PAH activity results in typical PKU while persistence of a residual enzyme activity gives rise to variant forms of the disease. We report here a 3-base pair in-frame deletion of the PAH gene (delta 194) in a mild variant, with markedly reduced affinity of the enzyme for phenylalanine (Km = 160 nM), and we provide functional evidence for responsibility of the deletion in the mutant phenotype. Since the deletion was located in the third exon of the gene, which presents no homology with other hydroxylases, we suggest that exon 3 is involved in the specificity of the enzyme for phenylalanine. Finally, since none of the 98 PKU patients tested were found to carry this particular deletion, our study suggests that this molecular event probably occurred recently on the background of a haplotype 2 gene in Portugal.
authors.affiliation: Unité de Recherches sur les Handicaps, Génétiques de l'Enfant, Institut National de la Santé et de la Recherche Médicale U-12, Hôpital des Enfants-Malades, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Caillaud
authors.forename: S
authors.initials: S
authors.lastname: Lyonnet
authors.forename: F
authors.initials: F
authors.lastname: Rey
authors.forename: D
authors.initials: D
authors.lastname: Melle
authors.forename: T
authors.initials: T
authors.lastname: Frebourg
authors.forename: M
authors.initials: M
authors.lastname: Berthelon
authors.forename: L
authors.initials: L
authors.lastname: Vilarinho
authors.forename: R
authors.initials: R
authors.lastname: Vaz Osorio
authors.forename: J
authors.initials: J
authors.lastname: Rey
authors.forename: A
authors.initials: A
authors.lastname: Munnich
mesh_terms: D001482:Base Composition; D001483:Base Sequence; D015152:Blotting, Northern; D002872:Chromosome Deletion; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D008969:Molecular Sequence Data; D010375:Pedigree; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D012313:RNA; D004247:DNA; D010651:Phenylalanine Hydroxylase