Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-09-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI166275 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sophie Karolczak |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:03Z |
| format | Article |
| id | doaj.art-abfd1acb3f994c4088ffb37901d8f229 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:03Z |
| publishDate | 2023-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-abfd1acb3f994c4088ffb37901d8f2292023-11-07T16:20:51ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-09-0113318Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathySophie KarolczakAshish R. DeshwarEvangelina AristeguiBinita M. KamathMichael W. LawlorGaia AndreolettiJonathan VolpattiJillian L. EllisChunyue YinJames J. DowlingX-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.https://doi.org/10.1172/JCI166275HepatologyMuscle biology |
| spellingShingle | 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 Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy The Journal of Clinical Investigation Hepatology Muscle biology |
| title | Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy |
| title_full | Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy |
| title_fullStr | Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy |
| title_full_unstemmed | Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy |
| title_short | Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy |
| title_sort | loss of mtm1 causes cholestatic liver disease in a model of x linked myotubular myopathy |
| topic | Hepatology Muscle biology |
| url | https://doi.org/10.1172/JCI166275 |
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