Dysregulated DNA methylation in the pathogenesis of Fabry disease

Shen, Jinsong; Balaji, Uthra; Shigeyasu, Kunitoshi; Okugawa, Yoshinaga; Jabbarzadeh-Tabrizi, Siamak; Day, Taniqua S.; Arning, Erland; Marshall, John; Cheng, Seng H.; Gu, Jin; Schiffmann, Raphael; Goel, Ajay

doi:10.1016/j.ymgmr.2022.100919

Cited by 2 publications

(2 citation statements)

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“…This study is in line with previous reports suggesting the involvement of epigenetic mechanisms in LSDs 2 , 3 . The observed alterations in DNA methylation and histone acetylation are consistent with studies conducted in other monogenic disorders 7 , 69 , 70 and highlight the potential role of these epigenetic marks in modulating disease phenotypes. However, further investigation is required to uncover the precise molecular events responsible for the alterations in DNA methylation and histone acetylation observed in MPS IIIB and MPS IVA.…”

Section: Discussionsupporting

confidence: 86%

“…Also, a study on methylation changes in the N-acetylgalactosamine-6-sulfate sulfatase ( GALNS ) gene involved in MPS IVA showed that transitional mutations that originated after deamination at the CpG dinucleotides were found in 29% of the point mutations in MPS IVA patients, suggesting that methylation in these CpG regions increase the probability of gene mutation 5 . Dysregulated DNA methylation in CpG sites throughout the genome and perturbed methionine cycle have also been observed in Fabry patients' endothelial cells 7 .…”

Section: Introductionmentioning

confidence: 99%

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Evidence of epigenetic landscape shifts in mucopolysaccharidosis IIIB and IVA

Vargas-López,

Prada,

Alméciga-Díaz

2024

Sci Rep

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Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function. Despite the monogenic nature, LSDs patients exhibit variable and heterogeneous clinical manifestations, prompting investigations into epigenetic factors underlying this phenotypic diversity. In this study, we focused on the potential role of epigenetic mechanisms in the pathogenesis of mucopolysaccharidosis IIIB (MPS IIIB) and mucopolysaccharidosis IVA (MPS IVA). We analyzed DNA methylation (5mC) and histone modifications (H3K14 acetylation and H3K9 trimethylation) in MPS IIIB and MPS IVA patients’ fibroblasts and healthy controls. The findings revealed that global DNA hypomethylation is present in cell lines for both diseases. At the same time, histone acetylation was increased in MPS IIIB and MPS IVA cells in a donor-dependent way, further indicating a shift towards relaxed open chromatin in these MPS. Finally, the constitutive heterochromatin marker, histone H3K9 trimethylation, only showed reduced clustering in MPS IIIB cells, suggesting limited alterations in heterochromatin organization. These findings collectively emphasize the significance of epigenetic mechanisms in modulating the phenotypic variations observed in LSDs. While global DNA hypomethylation could contribute to the MPS pathogenesis, the study also highlights individual-specific epigenetic responses that might contribute to phenotypic heterogeneity. Further research into the specific genes and pathways affected by these epigenetic changes could provide insights into potential therapeutic interventions for these MPS and other LSDs.

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