X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition
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 mu...
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Published in | Acta neuropathologica Vol. 144; no. 3; pp. 537 - 563 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.09.2022
Springer Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0001-6322 1432-0533 |
DOI: | 10.1007/s00401-022-02468-7 |