Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A (GLA) gene

BMC Genetics

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

 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.

【 图 表 】

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