title: The g.1170C>T polymorphism of the 5' untranslated region of the human alpha-galactosidase gene is associated with decreased enzyme expression--evidence from a family study.
abstract: Subnormal leukocyte α-galactosidase (α-Gal) activity was found during evaluation of an adolescent male with cryptogenic cerebrovascular small-vessel disease. The only molecular abnormality found was the g.1170C>T single-nucleotide polymorphism (SNP) in the 5' untranslated region of exon 1 in the α-Gal gene (GLA). Historically, this polymorphism has been considered to be biologically neutral. To test the hypothesis that the g.1170T allele might be associated with lower α-Gal expression, we genotyped GLA exon 1 and measured leukocyte and plasma α-Gal in the parents, brother and sister of the index case. The g.1170T allele co-segregated with a subnormal leukocyte α-Gal activity in the three siblings. Although plasma enzyme activities were within the normal range in all five relatives, the ranking of their values suggested a dosage effect of the g.1170T allele. Western blotting assays of leukocyte protein extracts showed that the relative expression of α-Gal in both the patient and his sister was significantly lower than in sex-matched hemizygous or homozygous controls for the g.1170C allele, either normalized to the β-actin immunoblot expression or standardized to a known amount of recombinant human α-Gal. These family data, in combination with results from a recent GLA SNP screening study among healthy Portuguese individuals, suggest that the g.1170C>T SNP may be co-dominantly associated with a relatively decreased GLA expression at the transcription and/or translation level. Larger population studies are needed to confirm these findings and to test the hypothesis that the GLA g.1170C>T may contribute to the multifactorial risk of ischaemic small-vessel cerebrovascular disease.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Porto, Alameda Hernâni Monteiro, 4200-319, Porto, Portugal. jpo@med.up.pt
authors.forename: J P
authors.initials: JP
authors.lastname: Oliveira
authors.forename: S
authors.initials: S
authors.lastname: Ferreira
authors.forename: C
authors.initials: C
authors.lastname: Reguenga
authors.forename: F
authors.initials: F
authors.lastname: Carvalho
authors.forename: J-E
authors.initials: JE
authors.lastname: Månsson
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002561:Cerebrovascular Disorders / Q000175:diagnosis* / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons; D000795:Fabry Disease / Q000150:complications / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D057898:Hemizygote; D006720:Homozygote; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D000519:alpha-Galactosidase