MUTATION AT THE PHENYLALANINE-HYDROXYLASE GENE (PAH) AND ITS USE TO DOCUMENT POPULATION GENETIC-VARIATION - THE QUEBEC EXPERIENCE

We describe variation at the PAH locus in the population of Quebec. We successfully analyzed 135 of 141 chromosomes from phenylketonuria (PK U) probands (95.7% of the sample), and eight additional chromosomes fr om a small number of probands with non-PKU hyperphenylalaninemia (HPA) . The full set of chromosomes harboured 45 different PAH mutations: i) seven polymorphisms (IVS2nt19, IVS3nt-22, IVS6nt-55, Q232Q, V245V, L3 85L, Y414Y); ii) four mutations causing non-PKU HPA (T92I, E390G, R408 Q, D415N); iii) 34 mutations causing PKU. Only six mutations (M1V, R26 1Q, F299C, S349P, R408W and IVS12nt1) occurred in the whole province a t relative frequencies > 5%; most are rare and probably identical by d escent. By studying associations of mutations with polymorphic haploty pe alleles, we found examples of mutations on different haplotypes tha t were identical by state, but not by descent because they were recurr ent mutations (E280K and R408W); and examples of mutations identical b oth by state and by descent because of intragenic recombination (S67P, G218V, V245A and IVS12nt1). Ten mutations were first described in Que bec and five are still unique there; three of these 'Quebec' mutations are reported here for the first time (c.125A-->T (K42I); [c.470G-->A; c.471A-->C] (R157N); c.707nt-55 (IVS6nt-55). The PAH mutations strati fy by geographic region and population, their distributions validating hypotheses about European range expansion to North America during thr ee separate phases of immigration and demographic expansion in the Que bec region over the past four centuries. The PAH homozygosity value (j ) is 0.06 for the total Quebec sample (0.5-0.08 by regions), and the c orresponding homoallelic fraction of mutant PAH genotypes is 24%. Thes e findings are a documentation of genetic diversity in the Quebec popu lation.