MOLECULAR-BASIS OF PHENYLKETONURIA IN VENEZUELA - PRESENCE OF 2 NOVELNULL MUTATIONS

This report describes the mutational spectrum and linked haplotypes of the phenylalanine hydroxylase gene in Venezuela. In this study we hav e detected European mutations such as IVS10nt-11, R243Q, and R408W on the same haplotype background (6.7, 1.8, and 2.3, respectively) as in Europe, In this sample, we have found two novel mutations: S349L detec ted in two homozygous siblings on the background of haplotype 6.7, and a small deletion, P3l4fsdelC, that results in a frameshift and a prem ature stop codon detected on the background of haplotype 4.3. The defi nite demonstration that mutation S349L results in a nonfunctional prot ein mas shown by expression analysis in prokaryotic and eukaryotic sys tems. This mutation results in an unstable phenylalanine hydroxylase ( PAH) protein completely devoid of enzymatic activity well correlated w ith the severe form of the disease exhibited by the homozygous patient s. (C) 1998 Wiley-Liss, Inc.