PREDICTION OF MULTIPLE HYPERMUTABLE CODONS IN THE HUMAN PAH GENE - CODON-280 CONTAINS RECURRENT MUTATIONS IN QUEBEC AND OTHER POPULATIONS

The predicted mutability profile (MUTPRED) of the phenylalanine hydrox ylase (PAH) gene shows that the 48 CpG sites (template and atemplate s trands) 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 a nd 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 concl ude that recurrent mutation is the likely origin of E280K in Quebec, T he PAH mutation database shows that the allele accounts for 1.5% of PK U chromosomes worldwide. (C) 1997 Wiley-Liss, Inc.