title: A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics.
abstract: Mutations in the gene encoding phenylalanine hydroxylase (PAH, EC 1.14.16.1) are associated with various degrees of hyperphenylalaninemia, including classical phenylketonuria (PKU). We examined the PAH gene in a Brazilian PKU family of African origin and identified three missense variants, R252W (c.754C --> T), K274E (c.820A --> G), and I318T (c.953T --> C), the two latter of which were transmitted in cis. Expression analyses in two different in vitro systems showed that I318T is associated with profoundly decreased enzyme activity, whereas the enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. Population studies have suggested that the K274E variant occurs on approximately 4% of African-American PAH alleles, whereas the neonatal screening incidence of PKU among African Americans is only 1:100,000. This is to our knowledge the first demonstration of a PAH missense variant with no apparent association to PAH deficiency. Awareness of this common variant may be helpful to laboratories that perform molecular diagnosis of PAH deficiency in populations of African origin.
authors.affiliation: The John F. Kennedy Institute, Glostrup, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Gjetting
authors.forename: A
authors.initials: A
authors.lastname: Romstad
authors.forename: J
authors.initials: J
authors.lastname: Haavik
authors.forename: P M
authors.initials: PM
authors.lastname: Knappskog
authors.forename: A X
authors.initials: AX
authors.lastname: Acosta
authors.forename: W A
authors.initials: WA
authors.lastname: Silva
authors.forename: M A
authors.initials: MA
authors.lastname: Zago
authors.forename: P
authors.initials: P
authors.lastname: Guldberg
authors.forename: F
authors.initials: F
authors.lastname: Güttler
mesh_terms: D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D044383:Black People; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D005091:Exons; D005192:Family Health; D006801:Humans; D007700:Kinetics; D020125:Mutation, Missense; D010649:Phenylalanine / Q000378:metabolism; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000175:diagnosis / Q000235:genetics; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D001741:Black or African American
chemical_list: D011994:Recombinant Proteins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase