Premium
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
Author(s) -
Oliveira J. P.,
Ferreira S.,
Reguenga C.,
Carvalho F.,
Månsson J.E.
Publication year - 2008
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-008-0972-0
Subject(s) - allele , biology , genetics , snp , exon , single nucleotide polymorphism , genotype , microbiology and biotechnology , gene , untranslated region , messenger rna
Summary 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.