Characterization of mutations art the mouse phenylalanine hydroxylase locus

Two genetic mouse models for human phenylketonuria have been characterized by DNA sequence analysis, For each, a distinct mutation was identified within the protein coding sequence of the phenylalanine hydroxylase gene. This establishes that the mutated locus is the same as that causing human phenylketonuria and allows a comparison between these mouse phenylketonuria models and the human disease. A genotype/phenotype relationship that is strikingly similar to the human disease emerges, underscoring the similarity of phenylketonuria in mouse and man. In PAH(ENU1), the phenotype is mild. The Pah(enu1) mutation predicts a conservative valine to alanine amino acid substitution and is located in exon 3, a gene region where serious mutations are rare in humans. In PAH(ENU2), the phenotype is severe. The Pah(enu2) mutation predicts a radical phenylalanine to serine substitution and is located in exon 7, a gene region where serious mutations are common in humans. In PAH(ENU2) the sequence information was used to devise a direct genotyping system based on the creation of a new Alw26I restriction endonuclease site. (C) 1997 Academic Press.