Prediction of multiple hypermutable codons in the human PAH gene: codon 280 contains recurrent mutations in Quebec...

The predicted mutability profile (MUTPRED) of the phenylalanine hydroxylase (PAH) gene shows that the 48 CpG sites (template and atemplate strands) are either empty of known mutations (7 sites), harbour "PKU" alleles involving CpG doublets (16 sites), or contain mutations that do not involve a C-->T or G-->A substitution in the doublet. These hypermutable sites harbour 32 different mutations in association with at least 66 different haplotypes and hyperphenylalaninemia. The E280K mutation in exon 7 of the PAH gene is a cause of phenylketonuria. It occurs on four different haplotypes in Europeans and on haplotypes 1 and 2 in Quebec. Whereas a single recombination event could explain the two haplotype associations in Quebec, the mutation does involve a CpG dinucleotide. By analyzing multiallelic markers 5' (STR) and 3' (VNTR) to the E280K allele on 12 mutant and 30 normal chromosomes, we conclude that recurrent mutation is the likely origin of E280K in Quebec. The PAH mutation database shows that the allele accounts for 1.5% of PKU chromosomes worldwide.