title: Phenylketonuria missense mutations in the Mediterranean.
abstract: Two missense mutations have been identified in the phenylalanine hydroxylase (PAH) genes of an Italian phenylketonuria (PKU) patient. Both mutations occurred in exon 7 of the PAH gene, resulting in the substitution of Trp for Arg at amino acid 252 (R252W) and of Leu for Pro (P281L) at amino acid 281 of the protein. Expression vectors containing either the normal human PAH cDNA or mutant cDNAs were constructed and transfected into cultured mammalian cells. Extracts from cells transfected with either mutant construct showed negligible enzyme activity and undetectable levels of immunoreactive PAH protein as compared to the normal construct. These results are compatible with the severe classical PKU phenotype observed in this patient. Population genetic studies in the Italian population revealed that both the R252W and the P281L mutations are in linkage disequilibrium with mutant restriction fragment length polymorphism (RFLP) haplotype 1, which is the most prevalent RFLP haplotype in this population. The R252W mutation is present in 10% and the P281L mutation is present in 20% of haplotype 1 mutant chromosomes. These mutations are both very rare among other European populations, suggesting a Mediterranean origin for these mutant chromosomes.
authors.affiliation: Howard Hughes Medical Institute, Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Y
authors.initials: Y
authors.lastname: Okano
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: R C
authors.initials: RC
authors.lastname: Eisensmith
authors.forename: R
authors.initials: R
authors.lastname: Longhi
authors.forename: E
authors.initials: E
authors.lastname: Riva
authors.forename: M
authors.initials: M
authors.lastname: Giovannini
authors.forename: R
authors.initials: R
authors.lastname: Cerone
authors.forename: C
authors.initials: C
authors.lastname: Romano
authors.forename: S L
authors.initials: SL
authors.lastname: Woo
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005091:Exons; D005260:Female; D005796:Genes; D005828:Genetics, Population; D006801:Humans; D007558:Italy; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D014162:Transfection
chemical_list: D010651:Phenylalanine Hydroxylase