Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy
Sophie Karolczak, … , Chunyue Yin, James J. Dowling
Sophie Karolczak, … , Chunyue Yin, James J. Dowling
Published July 25, 2023
Citation Information: J Clin Invest. 2023;133(18):e166275. https://doi.org/10.1172/JCI166275.
View: Text | PDF
Research Article Hepatology Muscle biology

Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

  • Text
  • PDF
Abstract

X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, 4 patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized what we believe to be a novel liver phenotype in a zebrafish model of this disease. Specifically, we found that loss-of-function mutations in mtm1 led to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosome-mediated trafficking of canalicular transporters. Using a reporter-tagged Mtm1 zebrafish line, we established localization of Mtm1 in the liver in association with Rab11, a marker of recycling endosomes, and canalicular transport proteins and demonstrated that hepatocyte-specific reexpression of Mtm1 could rescue the cholestatic phenotype. Last, we completed a targeted chemical screen and found that Dynasore, a dynamin-2 inhibitor, was able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate, for the first time to our knowledge, liver abnormalities that were directly caused by MTM1 mutation in a preclinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.

Authors

Sophie Karolczak, Ashish R. Deshwar, Evangelina Aristegui, Binita M. Kamath, Michael W. Lawlor, Gaia Andreoletti, Jonathan Volpatti, Jillian L. Ellis, Chunyue Yin, James J. Dowling

×

Figure 8

DNM2 inhibition rescues the mtm cholestatic phenotype.

Options: View larger image (or click on image) Download as PowerPoint
DNM2 inhibition rescues the mtm cholestatic phenotype.
A targeted panel ...
A targeted panel of chemicals was tested in mtm zebrafish, using the BODIPY assay as a screen for the cholestatic liver phenotype. For each chemical, the percentage of mtm zebrafish with positive staining in the gallbladder was measured as the readout (n = 10 per trial, with 1 replicate per trial). (A) Two DNM2 inhibitors, Dynasore (green arrow) and Dyngo-4a (pink arrow), were among the chemicals that produced the highest percentage of BODIPY+ larvae. (B) Validation of Dynasore combining 3 independent replicates of 10 larvae per replicate. Dynasore-treated mtm larvae had improved bile flux compared with their DMSO-treated mtm siblings (Dynasore = 30.6%, DMSO = 3.67%, P = 0.019, by 2-sided Fisher’s exact test) and did not differ significantly from their WT DMSO-treated siblings (WT percentage = 56.7%, Dynasore percentage = 30.6%, P = 0.13, 2-sided Fisher’s exact test). (C) Dynasore partially restored canalicular structure and transporter expression. Coimmunostaining was performed on whole-mount embryos either exposed to DMSO or treated with Dynasore. As expected, in DMSO-treated mtm zebrafish, essentially no Mdr1 staining was appreciated. In Dynasore-treated larvae, however, there was robust reexpression of Mdr1 and proper colocalization with Rab11. Scale bars: 20 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts