The modulatory effects of the polymorphisms in GLA 5¿-untranslated region upon gene expression are cell-type specific

• Type: Chapter or Part of a Book
• Date: 2015

Authors

Ferreira, S (Author) Other; reguenga, c (Author) FMUP; João Paulo Oliveira (Author) FMUP

Indexing

Scopus - 9 Citations

Other information

Authenticus ID: P-00S-2TF

DOI: 10.1007/8904_2015_424

Abstract (EN): Lysosomal ¿-galactosidase A (¿Gal) is the enzyme deficient in Fabry disease (FD). The 5¿-untranslated region (5¿UTR) of the ¿Gal gene (GLA) shows a remarkable degree of variation with three common single nucleotide polymorphisms at nucleotide positions c.-30G>A, c.-12G>A and c.-10C>T. We have recently identified in young Portuguese stroke patients a fourth polymorphism, at c.-44C>T, co-segregating in cis with the c.-12A allele. In vivo, the c.-30A allele is associated with higher enzyme activity in plasma, whereas c.-10T is associated with moderately decreased enzyme activity in leucocytes. Limited data suggest that c.-44T might be associated with increased plasma ¿Gal activity. We have used a luciferase reporter system to experimentally assess the relative modulatory effects on gene expression of the different GLA 5¿UTR polymorphisms, as compared to the wild-type sequence, in four different human cell lines. Group-wise, the relative luciferase expression patterns of the various GLA variant isoforms differed significantly in all four cell lines, as evaluated by non-parametric statistics, and were cell-type specific. Some of the post hoc pairwise statistical comparisons were also significant, but the observed effects of the GLA 5¿UTR polymorphisms upon the luciferase transcriptional activity in vitro did not consistently replicate the in vivo observations. These data suggest that the GLA 5¿UTR polymorphisms are possible modulators of the ¿Gal expression. Further studies are needed to elucidate the biological and clinical implications of these observations, particularly to clarify the effect of these polymorphisms in individuals carrying GLA variants associated with high residual enzyme activity, with no or mild FD clinical phenotypes. © SSIEM and Springer-Verlag Berlin Heidelberg 2015.

Language: English

Type (Professor's evaluation): Scientific