Abstract
Background: Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Gb3 accumulation was especially reported for the vascular endothelium in several organs. Methods: Three Fabry disease patients were screened using a micro-RNA screen. An in vitro approach in human endothelial cells was used to determine miRNA regulation by Gb3. Results: In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. We demonstrate in vitro in endothelial cells that Gb3 induced activation of NF-κB and activated downstream targets. In addition, NF-κB activity directly reduced let-7a and let-7d miRNA expression as inhibiting NF-kB nuclear entry abolished the Gb3 effects. Conclusion: We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients.
Highlights
Fabry disease is an X-linked inborn disease with a defective glycosphingolipid catabolism due to the deficient activity of α-galactosidase A [1]
To determine if Gb3 would have a direct effect on the composition of circulating micro-ribonucleic acids (miRNAs) in Fabry patients, we used a miRNA qPCR-based screening of 372 miRNAs in three previously treatment-naive patients before and during enzyme replacement therapy (ERT)
A miRNA screen in three human patients undergoing ERT for Fabry disease revealed an upregulation of let-7a and let-7d, which was previously demonstrated to be associated with inflammation [16]
Summary
Fabry disease is an X-linked inborn disease with a defective glycosphingolipid catabolism due to the deficient activity of α-galactosidase A [1]. This defect leads to an accumulation of respective substrates, mainly globotriaosylceramide (Gb3), in body fluids and cells [2]. Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Results: In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. Conclusion: We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients
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