RELATIVE FREQUENCY, HETEROGENEITY AND GEOGRAPHIC CLUSTERING OF PKU MUTATIONS IN NORWAY

We have analysed 236 Norwegian phenylketonuria (PKU) alleles by a comb ination 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 the se 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. Th e 8 most common mutations represented 83.5% of the PKU alleles, with s ingle allele frequencies ranging from 5.9 to 15.7%. Four of these muta tions (R261Q, R408W, Y414C, and IVS12nt1) 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, R158 Q, 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 Euro pean populations, suggesting that only a few of the mutations may repr esent recurrent mutations (<3.4%). Among 10 mutations only reported fo r our population, we detected 2 de novo mutations (0.8%) arisen in Nor way. From the birthplaces of the probands' grandparents, each mutation seemed to have an individual geographic distribution within Norway, w ith patterns of local mutation clustering. Our observations are compat ible with multiple founder effects and genetic drift for the distribut ion of PKU mutations within Norway.