BMC Genetics | |
Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A (GLA) gene | |
Pilar Giraldo1  Miguel Pocovi3  Jose C. Rodriguez-Rey4  Jose L. Capablo2  Jose C. Roche2  Luis Plaza5  Javier Perez-Lopez4  Pilar Irun3  Jorge J. Cebolla3  Javier Gervas-Arruga3  | |
[1] Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain;Neurology Department, Miguel Servet University Hospital, Zaragoza, Spain;Biochemistry and Molecular and Cellular Biology Department, Universidad de Zaragoza, Zaragoza, Spain;Molecular Biology Department, Cantabria University and IFIMAV, Santander, Spain;Anatomic Pathology Department, Miguel Servet University Hospital, Zaragoza, Spain | |
关键词: α-galactosidase A; Galactosphingolipids; Haplotypes; Fabry disease; GLA; | |
Others : 1224437 DOI : 10.1186/s12863-015-0267-z |
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received in 2015-04-09, accepted in 2015-08-25, 发布年份 2015 | |
【 摘 要 】
Background
Accumulation 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.
Results
CIH 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.
Conclusions
Thus, inheritance of the CIH caused an mRNA deregulation altering the GLA expression pattern, producing a tissue glycolipid storage.
【 授权许可】
2015 Gervas-Arruga et al.
【 预 览 】
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