The g.1170C&gt;T polymorphism of the 5′ untranslated region of the human alpha‐galactosidase gene is associated with decreased enzyme expression—Evidence from a family study

Oliveira, João Paulo; Ferreira, Susana; Reguenga, Carlos; Carvalho, Filipa; Månsson, Jan‐Eric

doi:10.1007/s10545-008-0972-0

Cited by 22 publications

(30 citation statements)

References 36 publications

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“…The amount of aGal identified by western blot analyses of leukocyte protein extracts was significantly lower in carriers of the c.-10T allele as compared to carriers of the WT allele (Oliveira et al 2008b). Experimental data (Samac et al 1998) have shown that sequence changes that increase the affinity of the GLA 5 0 UTR MDBP binding site for its cognate ligands exert a strong repressive effect upon gene expression.…”

Section: Discussionmentioning

confidence: 98%

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

2015

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Lysosomal a-galactosidase A (aGal) is the enzyme deficient in Fabry disease (FD). The 5 0 -untranslated region (5 0 UTR) of the aGal 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 aGal activity. We have used a luciferase reporter system to experimentally assess the relative modulatory effects on gene expression of the different GLA 5 0 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 0 UTR polymorphisms upon the luciferase transcriptional activity in vitro did not consistently replicate the in vivo observations. These data suggest that the GLA 5 0 UTR polymorphisms are possible modulators of the aGal 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.

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Section: Discussionmentioning

confidence: 98%

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

2015

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“…GLA gene mutations and sequence variants were identified by direct sequencing of polymerase chain reaction (PCR) or reverse transcription-PCR (RT-PCR) products, using a conventional Sanger method [40]. The blood sample processing and analytical protocols used for GLA genotyping have been previously reported [40].…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

“…The blood sample processing and analytical protocols used for GLA genotyping have been previously reported [40]. GLA sequence changes are described according to the most recent recommendations of the Human Genome Variation Society [HGVS; http://www.hgvs.org/mutnomen/recs-prot.html].…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Ferreira

Auray‐Blais

Boutin

et al. 2015

Clinica Chimica Acta

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Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study.

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“…Details of these laboratory methods have been formerly published. 14 The reference GLA gDNA and cDNA nucleotide sequences, respectively GenBank Version X14448.1 and RefSeq Version NM_000169.2, were obtained from the National Center for Biotechnology Information (Bethesda, Md; www.ncbi.nlm.nih.gov/entrez/). Mutations detected in the original GLA cDNA or gDNA analyses were confirmed in a duplicate PCR amplification of the corresponding exon using the stored gDNA samples.…”

Section: Laboratory Methodsmentioning

confidence: 99%

“…To this end, endonucleases HinfI and Hpy188III were selected with the NEBcutter software (http://tools.neb.com/NEBcutter2/), respectively to identify alleles p.R118C and p.D313Y. GLA exons 2 and 6 were PCRamplified as described 14 and the digestion of the corresponding amplicons was carried out according to the instructions of the enzyme manufacturer (New England BioLabs, Hitchin, UK). In the restriction analyses, gDNA samples of p.R118C or p.D313Y heterozygous carriers from the patient cohort were used as positive controls.…”

Section: Control Population and Screeningmentioning

confidence: 99%

Mutations of the GLA Gene in Young Patients With Stroke

Viana-Baptista

Ferreira

Pinho‐e‐Melo

et al. 2010

Stroke

109

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Background and Purpose— Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. Methods— During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. Results— Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte α-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). Conclusions— Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.

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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

Cited by 22 publications

References 36 publications

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

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

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Mutations of the GLA Gene in Young Patients With Stroke

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