ISSN:
1573-2665
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Human α-galactosidase A (EC 3.2.1.22; α-Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal α-galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). An unsually elevated level of plasma α-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 α-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 NFκB/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 α-Gal A activity from individuals with the -30G→A mutation had normal physical and kinetic properites. In vitro translation of mRNAs from the cloned normal and high plasma activity alleles resulted in similar levels of α-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 α-Gal A gene enhances transcription, presumably by interfering with the binding of negatively-acting transcription factors which normally decrease α-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 α-Gal A activity due to this variant allele.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1005366224351
