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.