The Modulatory Effects of the Polymorphisms in GLA 5′-Untranslated Region Upon Gene Expression Are Cell-Type Specific

  • Susana FerreiraEmail author
  • Carlos Reguenga
  • João Paulo Oliveira
Research Report
Part of the JIMD Reports book series (JIMD, volume 23)


Lysosomal α-galactosidase A (αGal) is the enzyme deficient in Fabry disease (FD). The 5′-untranslated region (5′UTR) of the αGal 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 αGal 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 αGal 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.


Jurkat Cell Fabry Disease Residual Enzyme Activity Relative Luciferase Activity Portuguese Population 
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These studies have been partially supported by a donation from Sanofi-Genzyme (Portugal) for research in Fabry disease. However, Sanofi-Genzyme was not involved in any way either with the design or the development of this study, including the analyses of the experimental data, or with the decision to publish their results.

We thank Deolinda Lima, M.D., Ph.D., for providing the facilities of the Laboratory of Support to Research in Molecular Medicine (LAIMM), at the Department of Experimental Biology, of the Faculty of Medicine, University of Porto (FMUP), Portugal, where most of the experimental work was performed.

We thank Ana Moço, MSc Student, from the Biocomposites Group, Institute of Biomedical Engineering (INEB), Faculty of Engineering, University of Porto (FEUP), Portugal, for generously providing the HDMEC cells; José Pedro Castro, Ph.D. Student, from the Department of Experimental Biology, Centre for Medical Research, FMUP, for generously providing the Jurkat cells; and Ana Grangeia, Ph.D., from the Genetics Department, FMUP, for generously providing the HEK-293 cells.

Supplementary material


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Susana Ferreira
    • 1
    Email author
  • Carlos Reguenga
    • 2
    • 3
  • João Paulo Oliveira
    • 1
    • 4
  1. 1.Department of Genetics, Faculty of MedicineUniversity of PortoPortoPortugal
  2. 2.Department of Experimental Biology, Faculty of MedicineUniversity of PortoPortoPortugal
  3. 3.Institute for Molecular and Cell BiologyPortoPortugal
  4. 4.Genetics Clinic, São João Hospital CentrePortoPortugal

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