ANALYSIS OF THE PHENYLALANINE-HYDROXYLASE GENE IN THE SPANISH POPULATION - MUTATION PROFILE AND ASSOCIATION WITH INTRAGENIC POLYMORPHIC MARKERS

The aim of this study was to characterize the phenylketonuria (PKU) al leles in the Spanish population, by both identifying the causative mut ations and analyzing the RFLP haplotypes and the VNTR and short-tandem -repeat alleles associated with the phenylalanine hydroxylase (PAH) ge ne. We have investigated 129 independent mutant chromosomes, using den aturing gradient gel electrophoresis (DGGE) and direct sequencing. Nin ety percent of the alleles were identified, and a total of 40 differen t mutations were detected. The mutational spectrum includes seven prev iously unreported mutations: P122Q, D129G, P147S, D151G, A165T, S196fs , and P407S. Seven mutations represent 43% of the Spanish PKU alleles, the most common being IVS10nt-11g-->a (14.7%), I65T (8.5%), and V388M (6.2%). The remaining 33 mutations are rare. The mutation profile and relative frequencies are markedly different from those in northern Eu rope, also showing unique features compared with those in other, south ern European populations. The association analysis with polymorphic ma rkers in the PAH gene provides valuable information for population-gen etic studies and investigation of the origins of the mutations. This s tudy may serve as reference in the analysis of the contemporary distri butions and frequencies of the PKU mutations in related populations, w ith particular relevance in Latin American countries.