Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria

In the present study, 115 Brazilian families with phenylketonuria (PKU), ma inly from the Southeast of the country, were studied using three laboratory methods (DGGE, SSCP, and sequencing). All 13 exons of the PAH gene were an alyzed, including the splicing sites and the promoter region. We identified 50 distinct mutations and characterized 91% of the mutant alleles. The fiv e most prevalent mutations of the 50 mutations identified (50% of the PKU a lleles) were IVS10nt-11G-->A (17.4%), followed by R261Q (12.2%), V388M (9.1 %), R252W (6.5%), and R270K (4.8%). The other mutations were rare. The muta tion spectrum included 10 novel mutations (IVS5nt-54A-->G, IVS6nt17G-->T, E 205A, F240S, K274E, I318T, L321L, C357G, IVS11nt17G-->A, and S411X). To cha racterize the origin and distribution of the PAH alleles we determined the association between the detected mutations and the PCR/RFLP haplotypes and VNTR alleles located on the PAH gene. For those patients whose mutant allel es were detected, we calculated the correlation with pretreatment phenylala nine levels, thus establishing a genotype/phenotype correlation. The presen t results confirm the marked heterogeneity observed at the PAH locus and co ntribute to the understanding of the distribution and frequency of PKU muta tions in the Brazilian population. Hum Mutat 17:122-130, 2001. (C) 2001 Wil ey-Liss, Inc.