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

Animals Humans Disease Models, Animal Membrane Transport Proteins / metabolism Muscle, Skeletal / metabolism Mutation Myopathies, Structural, Congenital / genetics Protein Tyrosine Phosphatases, Non-Receptor / genetics Zebrafish / genetics
Hepatology Monogenic diseases Muscle Biology

Journal

The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877

Informations de publication

Date de publication:
15 09 2023
Historique:
received: 13 10 2022
accepted: 19 07 2023
medline: 18 9 2023
pubmed: 25 7 2023
entrez: 25 7 2023
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1172/JCI166275 PMID: 37490339 PMC: PMC10503795
pubmed: 37490339
pii: 166275
doi: 10.1172/JCI166275
pmc: PMC10503795
doi:
pii:

Substances chimiques

Membrane Transport Proteins 0
Protein Tyrosine Phosphatases, Non-Receptor EC 3.1.3.48
MTM1 protein, zebrafish EC 3.1.3.48

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NIDDK NIH HHS
ID : P30 DK078392
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117266
Pays : United States

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Auteurs

Sophie Karolczak (S)

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Molecular Genetics, The University of Toronto, Toronto, Ontario, Canada.

Ashish R Deshwar (AR)

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Clinical and Metabolic Genetics and.

Evangelina Aristegui (E)

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Binita M Kamath (BM)

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.

Michael W Lawlor (MW)

Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Translational Science Laboratory, Milwaukee, Wisconsin, USA.

Gaia Andreoletti (G)

Astellas Gene Therapies, San Francisco, California, USA.

Jonathan Volpatti (J)

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Jillian L Ellis (JL)

Division of Gastroenterology, Hepatology and Nutrition and Division of Developmental Biology and.

Chunyue Yin (C)

Division of Gastroenterology, Hepatology and Nutrition and Division of Developmental Biology and.
Center for Undiagnosed and Rare Liver Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

James J Dowling (JJ)

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Molecular Genetics, The University of Toronto, Toronto, Ontario, Canada.
Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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