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

  • Short Report
  • Published:
Journal of Inherited Metabolic Disease

Summary

Background:

The α-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 α-galactosidase (α-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 α-Gal expression.

Subjects and methods:

Plasma and leukocyte α-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 α-Gal activity in dried blood spots lower than 2 SD below the cohort average.

Results and conclusions:

Mean α-Gal leukocyte activity was ∼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 α-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 α-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 α-Gal activity than genetically comparable males.

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Fig. 1

Abbreviations

α-Gal:

α-galactosidase

GLA :

α-galactosidase gene

β-Gal:

β-galactosidase

dNTP:

deoxyribonucleotide triphosphate

EDTA:

ethylenediaminetetraacetic acid

MDBP:

methylated DNA-binding protein

NS:

not significant [statistically]

PCR:

polymerase chain reaction

SNP:

single-nucleotide polymorphism

SSCP:

single-strand conformation polymorphisms

SDS:

sodium dodecyl sulfate

SD:

standard deviation

Taq:

Thermophilus aquaticus

5′ UTR:

5′ untranslated region

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Acknowledgements

This study was partially supported by a grant from Genzyme Corporation. We thank Rob Pomponio, PhD, Genzyme Corporation, for critically reviewing the manuscript, and Hans Ebels, MD, Genzyme Europe BV, for editorial assistance.

Parts of these data were presented at the ‘7th European Round Table on Fabry Disease’, 27–28 October 2006, Barcelona, Spain, and published as an abstract in Clinical Therapeutics 2007; 9(Supplement A).

We are grateful to the medical students, the patient and his relatives who have made this study possible.

Author information

Authors and Affiliations

  1. Serviço de Genética, Faculdade de Medicina, Universidade do Porto, Alameda Hernâni Monteiro, 4200-319, Porto, Portugal

    J. P. Oliveira, S. Ferreira, J. Barceló & F. Carvalho

  2. UNILIPE, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal

    P. Gaspar & M. C. Sá Miranda

  3. Neurochemistry Laboratory Medicine, Clinical Chemistry, Sahlgren’s University Hospital, SE-431 80, Molndal, Sweden

    J.-E. Månsson

Authors
  1. J. P. Oliveira
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  2. S. Ferreira
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  3. J. Barceló
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  4. P. Gaspar
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  5. F. Carvalho
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  6. M. C. Sá Miranda
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  7. J.-E. Månsson
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Corresponding author

Correspondence to J. P. Oliveira.

Additional information

Communicating editor: Ed Wraith

Competing interests: J. P. Oliveira and J.-E. Månsson are members of the European Advisory Board of the ‘Fabry Registry’, a worldwide database of patients with Fabry disease sponsored by Genzyme Corporation, and have received grants for investigation activities from Genzyme Corporation. M. C. Sá Miranda has received grants for investigation activities from Genzyme Corporation.

References to electronic databases: α-Galactosidase: http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/2/1/22.html. Fabry disease: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301500. GLA:http://www.genenames.org/data/hgnc_data.php?hgnc_id=4296; GLA gene sequence: GenBank accession no. X16889, version 1: http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=31755. GLA cDNA sequence: GenBank accession no. NM_000169, version 2, http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=125661058. UTR Scan program: http://www.ba.itb.cnr.it/BIG/UTRScan. RNAstructure software: http://rna.chem.rochester.edu.

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Oliveira, J.P., Ferreira, S., Barceló, J. et al. Effect of single-nucleotide polymorphisms of the 5′ untranslated region of the human α-galactosidase gene on enzyme activity, and their frequencies in Portuguese caucasians. J Inherit Metab Dis 31 (Suppl 2), 247–253 (2008). https://doi.org/10.1007/s10545-008-0818-9

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  • DOI: https://doi.org/10.1007/s10545-008-0818-9

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