title: A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in north African Jews with phenylketonuria.
abstract: The majority of hyperphenylalaninemias (HPAs) result from mutations at the gene for phenylalanine hydroxylase (PAH). The broad phenotypic variability of these conditions, ranging from phenylketonuria (PKU) to mild benign HPA, is underlain by a wide spectrum of mutations giving rise to various genotypic combinations. Mutant PAH alleles, labeled by specific polymorphic haplotypes and mutations, are becoming useful markers in human population genetics. We report here a mutant PAH allele found in Jews from Morocco and Tunisia, marked by haplotype 4 and a missense mutation, TCASer-->CCAPro, at codon 349 in exon 10 of the gene. In vitro expression of the mutation showed normal levels of mRNA with virtually no enzymatic activity or protein immunoreactivity, pointing to a highly unstable protein. A homozygote for this mutation showed the most severe ("classical") type of PKU, while compound heterozygotes showed two other types of HPA--"atypical" PKU and "high benign" HPA--illustrating the interplay between different mutations that gives rise to various HPAs.
authors.affiliation: Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Weinstein
authors.forename: R C
authors.initials: RC
authors.lastname: Eisensmith
authors.forename: V
authors.initials: V
authors.lastname: Abadie
authors.forename: S
authors.initials: S
authors.lastname: Avigad
authors.forename: S
authors.initials: S
authors.lastname: Lyonnet
authors.forename: G
authors.initials: G
authors.lastname: Schwartz
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: S L
authors.initials: SL
authors.lastname: Woo
authors.forename: Y
authors.initials: Y
authors.lastname: Shiloh
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics*; D008969:Molecular Sequence Data; D009018:Morocco / Q000208:ethnology; D016297:Mutagenesis, Site-Directed; D010649:Phenylalanine / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D014416:Tunisia / Q000208:ethnology
chemical_list: D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase