Relative frequency, heterogeneity and geographic clustering of PKU mutations in Norway

We have analysed 236 Norwegian phenylketonuria (PKU) alleles by a combination of mutation scanning methods, restriction enzyme-based assays and DNA sequencing. Thirty-three different mutations constituted 99.6% of all mutant alleles (only 1 allele remains unidentified), 23 of these have been identified also in other European countries. Twenty were predicted missense mutations, 6 splice mutations, 4 nonsense mutations and 2 deletion mutations and 1 mutation disrupted the start codon. The 8 most common mutations represented 83.5% of the PKU alleles, with single allele frequencies ranging from 5.9 to 15.7%. Four of these mutations (R261Q, R408W, Y414C, and 1VS12nt1) are commonly occurring also in PKU patients in other European countries, while the other 4 (G46S, G272X, F299C, and R408Q) have higher frequencies in Norway than in any other country studied. Six mutations (I65T, L249F, P281L, Y356X, R158Q, and R252W) have frequencies between 0.8% and 2.1%, and 19 mutations were encountered only once. The majority of PKU mutations were found on the same RFLP/VNTR haplotype backgrounds in Norway as in other European populations, suggesting that only a few of the mutations may represent recurrent mutations (< 3.4%). Among 10 mutations only reported for our population, we detected 2 de novo mutations (0.8%) arisen in Norway. From the birthplaces of the probands' grandparents, each mutation seemed to have an individual geographic distribution within Norway, with patterns of local mutation clustering. Our observations are compatible with multiple founder effects and genetic drift for the distribution of PKU mutations within Norway.