Effect of single-nucleotide polymorphisms of the 5' untranslated region of the human alpha-galactosidase gene on enzyme activity, and their frequencies in Portuguese caucasians.

• BACKGROUND: The alpha-galactosidase gene (GLA) has three single-nucleotide polymorphisms in the 5' untranslated region of exon 1, respectively g.1150G>A, g.1168G>A, g.1170C>T. The g.1150A allele is associated with increased plasma alpha-galactosidase (alpha-Gal) activity in hemizygotes, while the others are regarded as biologically neutral. The primary goal of this investigation was to test the hypothesis, raised by a clinical observation and results of a family study, that the g.1170T allele polymorphism is associated with lower alpha-Gal expression. SUBJECTS AND METHODS: Plasma and leukocyte alpha-Gal activities were assayed in unrelated healthy young adults of both sexes, who had been genotyped for GLA exon 1, and enzyme activity values in carriers of any of the polymorphisms were compared to those of individuals with the standard genotype; GLA exon 1 was genotyped in males who had alpha-Gal activity in dried blood spots lower than 2 SD below the cohort average. RESULTS AND CONCLUSIONS: Mean alpha-Gal leukocyte activity was approximately 25% higher in subjects with the g.1170C or CC genotype than in those with the alternative genotypes (p < 0.05). The frequency of the g.1170T allele in subjects with low alpha-Gal activity in dried blood spots was 4-fold higher (p < 0.05) than in the general population. As in hemizygotes, the g.1150A heterozygote identified in this study had plasma alpha-Gal activity more than 2-fold above the normal mean. The g.1168A allele did not affect enzyme activity. Surprisingly, females with the standard GLA exon 1 genotype had significantly higher plasma alpha-Gal activity than genetically comparable males.

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