X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition.
Acta Neuropathol
; 144(3): 537-563, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35844027
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pez Cebra
/
Miopatías Estructurales Congénitas
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Acta Neuropathol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Canadá