Molecular characterization of PKU allele prevalent in southern Europe and Ireland.

A novel substitution has been characterized in the phenylalanine hydroxylase (PAH) gene that is linked exclusively to mutant haplotype 6, which is prevalent in southern Europe but rare in northern and eastern Europe. It is a G-to-A transition in intron 10, 11 bases from exon 11. This substitution creates an additional AG dinucleotide, which may serve as a cryptic splice acceptor site. Individuals who bear this substitution in the homozygous state have a severe PKU phenotype with pretreatment serum phenylalanine levels over 1200 mumol/liter. The frequency and distribution of this substitution among European populations suggests two possible founding populations, one being Middle Eastern and the other Roman. The use of this substitution as a marker to identify PKU chromosomes will be an invaluable aid to carrier screening and prenatal diagnosis in populations where mutant haplotype 6 is prevalent.