X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition.
Jonathan R VolpattiMehdi M Ghahramani-SenoMélanie MansatNesrin SabhaEge SarikayaSarah J GoodmanEric Chater-DiehlAlper CelikEmanuela PanniaCarine FromentLucie Combes-SoiaNika MaaniKyoko E YukiGaëtan ChicanneLiis Uusküla-ReimandSimon MonisSana Akhtar AlviCasie A GenettiBernard PayrastreAlan H BeggsCarsten G BonnemannFrancesco MuntoniMichael D WilsonRosanna WeksbergJulien ViaudJames E DowlingPublished in: Acta neuropathologica (2022)
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.
Keyphrases
- dna methylation
- genome wide
- gene expression
- end stage renal disease
- randomized controlled trial
- newly diagnosed
- ejection fraction
- late onset
- chronic kidney disease
- histone deacetylase
- prognostic factors
- high throughput
- machine learning
- mouse model
- copy number
- emergency department
- drug induced
- patient reported
- neural network