Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A GLA geneReportar como inadecuado

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BMC Genetics

, 16:109

Functional genetics


BackgroundAccumulation of galactosphingolipids is a general characteristic of Fabry disease, a lysosomal storage disorder caused by the deficient activity of α-galactosidase A encoded by the GLA gene. Although many polymorphic GLA haplotypes have been described, it is still unclear whether some of these variants are causative of disease symptoms. We report the study of an inheritance of a complex intronic haplotype CIH c.-10C > T, c.369 + 990C > A, c.370-81 370-77delCAGCC, c.640-16A > G, c.1000-22C > T within the GLA gene associated with Fabry-like symptoms and galactosphingolipid accumulation.

We analysed α-Gal A activity in plasma, leukocytes and skin fibroblasts in patients, and measured accumulation of galactosphingolipids by enzymatic methods and immunofluorescence techniques. Additionally, we evaluated GLA expression using quantitative PCR, EMSA, and cDNA cloning.

ResultsCIH carriers had an altered GLA expression pattern, although most of the carriers had high residual enzyme activity in plasma, leukocytes and in skin fibroblasts. Nonetheless, CIH carriers had significant galactosphingolipid accumulation in fibroblasts in comparison with controls, and also glycolipid deposits in renal tubules and glomeruli. EMSA assays indicated that the c.-10C > T variant in the promoter affected a nuclear protein binding site.

ConclusionsThus, inheritance of the CIH caused an mRNA deregulation altering the GLA expression pattern, producing a tissue glycolipid storage.

KeywordsGLA Fabry disease Haplotypes Galactosphingolipids α-galactosidase A AbbreviationsGLAAlfa galactosidase gene

FDFabry disease




α-Gal Aα-galactosidase A

CIHComplex intronic haplotype

TNFαTumor necrosis factor alpha

LAMP1Lysosomal-associated membrane protein 1

DGJ1-deoxygalactonojirimycin hydrochloride


PCRPolymerase chain reaction

RT-PCRReverse transcription polymerase chain reaction

MLPAMultiplex ligand probe amplification

FBSFetal bovine serum

DMEMDulbecco’s modified Eagle’s medium

qPCRQuantitative real-time PCR

EMSAElectrophoretic mobility shift assay

SSSSplice-site score

MRIMagnetic resonance image

LVLeft ventricle

LVEFLeft ventricular ejection fraction

MIMitral insufficiency

AIAortic insufficiency

QSTQuantitative sensory test

RQRelative quantification

WtWild type

SNPSingle nucleotide polymorphism

snRNASmall nuclear RNA

SNAP-CSmall nuclear RNA activating protein complex

XBBFX box-binding factors

DMRTDoublesex-mab-3 related

TBPTATA binding proteins

Electronic supplementary materialThe online version of this article doi:10.1186-s12863-015-0267-z contains supplementary material, which is available to authorized users.

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Autor: Javier Gervas-Arruga - Jorge J. Cebolla - Pilar Irun - Javier Perez-Lopez - Luis Plaza - Jose C. Roche - Jose L. Capablo


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