IN-VITRO EXPRESSION ANALYSIS OF MUTATIONS IN PHENYLALANINE-HYDROXYLASE - LINKING GENOTYPE TO PHENOTYPE AND STRUCTURE TO FUNCTION

Mutations in the human phenylalanine hydroxylase gene (PAH) altering t he expressed cDNA nucleotide sequence (GenBank U49897) can impair acti vity of the corresponding enzyme product (hepatic phenylalanine hydrox lase, PAH) and cause hyperphenylalaninemia (HPA), a metabolic phenotyp e for which the major disease form is phenylketonuria (PKU; OMIM 26160 0), In vitro expression analysis of inherited human mutations in eukar yotic, prokaryotic, and cell-free systems is informative about the mec hanisms of mutation effects on enzymatic activity and their predicted effect on the metabolic phenotype, Corresponding analysis of site-dire cted mutations in rat Pah cDNA has assigned critical functional roles to individual amino acid residues within the best understood species o f phenylalanine hydroxylase, Data on in vitro expression of 35 inherit ed human mutations and 22 created rat mutations are reviewed here, The core data are accessible at the PAH Mutation Analysis Consortium Web site (http://www.mcgill.ca/pahdb). Hum Mutat 11:4-17, 1998. (C) 1998 W iley-Liss, Inc.