PUBLICATION
X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition
- Authors
- Volpatti, J.R., Ghahramani-Seno, M.M., Mansat, M., Sabha, N., Sarikaya, E., Goodman, S.J., Chater-Diehl, E., Celik, A., Pannia, E., Froment, C., Combes-Soia, L., Maani, N., Yuki, K.E., Chicanne, G., Uusküla-Reimand, L., Monis, S., Alvi, S.A., Genetti, C.A., Payrastre, B., Beggs, A.H., Bonnemann, C.G., Muntoni, F., Wilson, M.D., Weksberg, R., Viaud, J., Dowling, J.J.
- ID
- ZDB-PUB-220720-7
- Date
- 2022
- Source
- Acta Neuropathologica 144(3): 537-563 (Journal)
- Registered Authors
- Beggs, Alan H., Dowling, Jim, Volpatti, Jonathan
- Keywords
- Congenital myopathies, Drug discovery, Epigenetics, X-linked myotubular myopathy
- Datasets
- GEO:GSE210642
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Epigenesis, Genetic
- Mice
- Muscle, Skeletal/metabolism
- Myopathies, Structural, Congenital*/drug therapy
- Myopathies, Structural, Congenital*/genetics
- Myopathies, Structural, Congenital*/metabolism
- Protein Tyrosine Phosphatases, Non-Receptor/genetics
- Protein Tyrosine Phosphatases, Non-Receptor/metabolism
- Valproic Acid/metabolism
- Valproic Acid/pharmacology
- Zebrafish*/metabolism
- PubMed
- 35844027 Full text @ Acta Neuropathol.
Citation
Volpatti, J.R., Ghahramani-Seno, M.M., Mansat, M., Sabha, N., Sarikaya, E., Goodman, S.J., Chater-Diehl, E., Celik, A., Pannia, E., Froment, C., Combes-Soia, L., Maani, N., Yuki, K.E., Chicanne, G., Uusküla-Reimand, L., Monis, S., Alvi, S.A., Genetti, C.A., Payrastre, B., Beggs, A.H., Bonnemann, C.G., Muntoni, F., Wilson, M.D., Weksberg, R., Viaud, J., Dowling, J.J. (2022) X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition. Acta Neuropathologica. 144(3):537-563.
Abstract
X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping