Human alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A) is the lysosomal 
exoglycosidase responsible for the hydrolysis of terminal alpha-galactosyl 
residues from glycoconjugates and is the defective enzyme causing Fabry disease 
(McKusick 301500). An unusally elevated level of plasma alpha-Gal A activity (> 
2.5 times the normal mean) was detected in two unrelated normal males and the 
elevated activities were inherited as X-linked traits in their families. 
Sequencing of the alpha-Gal A coding region, intron/exon boundaries and 
5'-flanking region from the proband identified a single mutation, a G-->A 
transition 30 nt upstream from the initiation of translation codon in exon 1. 
The -30G-->A mutation occurred in a putative NF kappa B/Ets consensus binding 
site that was recently shown to inhibit protein binding to the 5'-untranslated 
region of the gene, providing a possible explanation for its high activity. To 
further characterize the mutation, the mRNA and protein expressed by this 
variant allele were studied. Purified plasma and lymphoblast alpha-Gal A 
activity from individuals with the -30G-->A mutation had normal physical and 
kinetic properties. In vitro translation of mRNAs from the cloned normal and 
high plasma activity alleles resulted in similar levels of alpha-Gal A protein, 
indicating that this mutation did not enhance translation. These findings 
suggest that the -30G-->A mutation in the 5'-untranslated region of the 
alpha-Gal A gene enhances transcription, presumably by interfering with the 
binding of negatively-acting transcription factors which normally decrease 
alpha-Gal A expression in various cells. Preliminary studies of the frequency of 
the -30G-->A mutation in 395 unrelated normal males of mixed ancestry revealed 
two additional unrelated individuals who had high plasma enzymatic activity and 
the mutation, confirming the effect of this mutation on enzyme expression and 
suggesting that about 0.5% of normal individuals have high plasma alpha-Gal A 
activity due to this variant allele.