title: [Phenotypic expression of 12 mutations of the phenylalanine hydroxylase gene].
abstract: BACKGROUND
  Several mutations in the human phenylalanine hydroxylase (PAH) gene have been described and it may be interesting to tentatively correlate mutant genotypes and clinical phenotypes of phenylketonuria (PKU).
  
  
  METHODS
  Twelve mutations were searched for using classical techniques of molecular biology in a total of 126 patients. 3 phenotypes were arbitrarily defined: typical PKU, atypical PKU or Mediterranean form, and persistent mild hyperphenylalaninemia. The patients were classified according to the residual in vivo PAH activity.
  
  
  RESULTS
  Mutations were found in 64 patients. One mutation was found in each of the 2 alleles in 20 children. Only one mutation could be identified in the other 44. Only 45 children could be assigned to a phenotype. Mutations leading to total loss of PAH activity were associated with typical PKU (in homozygotes or compound heterozygotes). Mutations leading to residual PAH activity were associated in homozygotes with atypical PKU; they were also associated in compounded heterozygotes with atypical PKU, irrespective of the fact that the other allele suppressed enzyme activity or was unknown. A mutation which changed the affinity of PAH for phenylalanine was associated with mild hyperphenylalaninemia.
  
  
  CONCLUSIONS
  The clinical heterogeneity of PKU can be correlated with identified mutations of the human PAH gene. Molecular studies do not help to predict either the phenotype or the long-term outcome. However, description of the biochemical changes combined with identification of the mutation should lead to a better understanding of consequences of mutation for PAH activity.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant (INSERM U12), Hôpital des Enfants-Malades, Paris.
authors.forename: F
authors.initials: F
authors.lastname: Rey
authors.forename: V
authors.initials: V
authors.lastname: Abadie
authors.forename: S
authors.initials: S
authors.lastname: Lyonnet
authors.forename: M
authors.initials: M
authors.lastname: Berthelon
authors.forename: C
authors.initials: C
authors.lastname: Caillaud
authors.forename: D
authors.initials: D
authors.lastname: Melle
authors.forename: P
authors.initials: P
authors.lastname: Labrune
authors.forename: J M
authors.initials: JM
authors.lastname: Saudubray
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: J
authors.initials: J
authors.lastname: Rey
mesh_terms: D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D010641:Phenotype; D010649:Phenylalanine / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics
chemical_list: D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase
vernacular_title: Expression phénotypique de 12 mutations du gène de la phénylalanine hydroxylase.