A Phenylalanine Hydroxylase Amino Acid Polymorphism with Implications for Molecular Diagnostics

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....

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Published in:	Molecular genetics and metabolism Vol. 73; no. 3; pp. 280 - 284
Main Authors:	Gjetting, Torben, Romstad, Anne, Haavik, Jan, Knappskog, Per M., Acosta, Angelina X., Silva, W.Araújo, Zago, Marco A., Guldberg, Per, Gttler, Flemming
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2001
Subjects:	Alleles Amino Acid Metabolism, Inborn Errors - diagnosis Amino Acid Metabolism, Inborn Errors - genetics amino acid polymorphism Black or African American Black People Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Escherichia coli - metabolism Exons Family Health Humans in vitro expression Kinetics Mutation, Missense Phenylalanine - metabolism phenylalanine hydroxylase Phenylalanine Hydroxylase - genetics phenylketonuria Phenylketonurias - diagnosis Phenylketonurias - genetics Polymorphism, Genetic Recombinant Proteins - metabolism phenylketonuria amino acid polymorphism phenylalanine hydroxylase in vitro expression
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1096-7192 1096-7206
DOI:	10.1006/mgme.2001.3180