Dysregulated DNA methylation in the pathogenesis of Fabry disease

Mol Genet Metab Rep. 2022 Sep 26;33:100919. doi: 10.1016/j.ymgmr.2022.100919.

PMID: 36186841

Jin-Song Shen, Uthra Balaji, Kunitoshi Shigeyasu

Highlights: This study provides evidence that α-galactosidase A deficiency and glycosphingolipid storage may affect DNA methylation homeostasis and highlights the importance of epigenetics in the pathogenesis of Fabry disease.

Abstract

Background: A deficiency of α-galactosidase A results in a buildup of glycosphingolipids with terminal α-D-galactosyl residues, and this accumulation is what causes Fabry disease, an X-linked lysosomal storage disorder. Uncertainty exists regarding the biochemical mechanism by which the aberrant glycosphingolipid metabolism in Fabry disease leads to multisystem dysfunction.

Objective: This study aimed to ascertain whether abnormal DNA methylation contributes to the onset of the disease. The current study investigated whether altering α-galactosidase A activity and glycosphingolipid metabolism had an impact on DNA methylation using isogenic cellular models obtained from endothelial cells from Fabry patients.

Results: Changes in α-galactosidase A activity were linked to dramatically changed DNA methylation in the androgen receptor promoter, according to data from bisulfite pyrosequencing. This effect was extremely CpG loci-specific. Studies using methylation arrays demonstrated a relationship between the differential methylation of many CpG sites throughout the genome and α-galactosidase A activity and glycosphingolipid levels. 15 signaling pathways were shown to be potentially vulnerable to methylation changes in Fabry disease. 21 genes were discovered with variable mRNA expression and methylation by integrating RNA sequencing data. The expression of the collagen type IV alpha 1 and alpha 2 genes was upregulated, and their methylation levels were decreased. Methionine levels were raised in Fabry patient cells and Fabry mouse tissues, pointing to the possibility that the observed dysregulated methylation patterns are a result of a disturbed methionine cycle.

Conclusion: In conclusion, this study underscores the significance of epigenetics in the etiology of Fabry disease and, potentially, other lysosomal storage disorders and offers evidence that α -galactosidase A deficiency and glycosphingolipid accumulation may impact DNA methylation homeostasis.

Keywords: DNA methylation, Fabry disease, Globotriaosylceramide, α-Galactosidase A