Volpatti, Jonathan R;
Ghahramani-Seno, Mehdi M;
Mansat, Mélanie;
Sabha, Nesrin;
Sarikaya, Ege;
Goodman, Sarah J;
Chater-Diehl, Eric;
... Dowling, James J; + view all
(2022)
X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition.
Acta Neuropathologica
10.1007/s00401-022-02468-7.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition |
| Location: | Germany |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s00401-022-02468-7 |
| Publisher version: | https://doi.org/10.1007/s00401-022-02468-7 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Congenital myopathies, Drug discovery, Epigenetics, X-linked myotubular myopathy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10152846 |
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