Characterization of mutations at the mouse phenylalanine hydroxylase locus

Abstract

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 PAHENU1, the phenotype is mild. The Pahenu1 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 PAHENU2, the phenotype is severe. The Pahenu2 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 PAHENU2, the sequence information was used to devise a direct genotyping system based on the creation of a new Alw26I restriction endonuclease site.