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, though AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, four patients with XLMTM treate...

Full description

Saved in:
Bibliographic Details
Published inThe Journal of clinical investigation Vol. 133; no. 18; pp. 1 - 13
Main Authors Karolczak, Sophie, Deshwar, Ashish R, Aristegui, Evangelina, Kamath, Binita M, Lawlor, Michael W, Andreoletti, Gaia, Volpatti, Jonathan R, Ellis, Jillian L, Yin, Chunyue, Dowling, James J
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 15.09.2023
Subjects
Acids
Animal models
Bile
Bile ducts
Biomedical research
Causes of
Complications and side effects
Congenital diseases
Danio rerio
Dynamin
Endosomes
Gallbladder
Gallbladder diseases
Gene therapy
Genetic aspects
Genotype & phenotype
Hepatology
Lipids
Liver diseases
Localization
MTM1 gene
Muscle biology
Mutation
Myopathy
Neuromuscular diseases
Ostomy
Pathology
Phenotypes
Protein transport
Protein turnover
Proteins
Zebrafish
Canada
Muscle Biology
Hepatology
Monogenic diseases
Online AccessGet full text

Cover

Abstract X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, though AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, four 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 a novel liver phenotype in a zebrafish model of this disease. Specifically, we have found that loss-of-function mutations in mtm1 lead to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomal-mediated trafficking of canalicular transporters. Using a reporter tagged Mtm1 zebrafish line, we have established localization of Mtm1 in the liver in association with Rab11 and canalicular transport proteins, and demonstrated that hepatocyte specific re-expression of Mtm1 can rescue the cholestatic phenotype. Lastly, we completed a targeted chemical screen, and found that Dynasore, a dynamin II inhibitor, is able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate for the first time liver abnormalities that are directly caused by MTM1 mutation in a pre-clinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.
AbstractList X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, though AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, four 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 a novel liver phenotype in a zebrafish model of this disease. Specifically, we have found that loss-of-function mutations in mtm1 lead to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomal-mediated trafficking of canalicular transporters. Using a reporter tagged Mtm1 zebrafish line, we have established localization of Mtm1 in the liver in association with Rab11 and canalicular transport proteins, and demonstrated that hepatocyte specific re-expression of Mtm1 can rescue the cholestatic phenotype. Lastly, we completed a targeted chemical screen, and found that Dynasore, a dynamin II inhibitor, is able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate for the first time liver abnormalities that are directly caused by MTM1 mutation in a pre-clinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.
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.
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.
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 mtml led to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomemediated trafficking of canaliculartransporters. 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 canaliculartransport 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 predinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.
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.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.
Audience Academic
Author Deshwar, Ashish R
Volpatti, Jonathan R
Karolczak, Sophie
Dowling, James J
Kamath, Binita M
Andreoletti, Gaia
Aristegui, Evangelina
Yin, Chunyue
Lawlor, Michael W
Ellis, Jillian L
AuthorAffiliation 5 Medical College of Wisconsin, Milwaukee, Wisconsin, USA
6 Translational Science Laboratory, Milwaukee, Wisconsin, USA
8 Division of Gastroenterology, Hepatology and Nutrition and Division of Developmental Biology and
2 Department of Molecular Genetics, The University of Toronto, Toronto, Ontario, Canada
4 Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
10 Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada
1 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
7 Astellas Gene Therapies, San Francisco, California, USA
9 Center for Undiagnosed and Rare Liver Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
3 Division of Clinical and Metabolic Genetics and
AuthorAffiliation_xml – name: 1 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
– name: 2 Department of Molecular Genetics, The University of Toronto, Toronto, Ontario, Canada
– name: 9 Center for Undiagnosed and Rare Liver Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
– name: 6 Translational Science Laboratory, Milwaukee, Wisconsin, USA
– name: 4 Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
– name: 5 Medical College of Wisconsin, Milwaukee, Wisconsin, USA
– name: 3 Division of Clinical and Metabolic Genetics and
– name: 10 Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada
– name: 7 Astellas Gene Therapies, San Francisco, California, USA
– name: 8 Division of Gastroenterology, Hepatology and Nutrition and Division of Developmental Biology and
Author_xml – sequence: 1
  givenname: Sophie
  surname: Karolczak
  fullname: Karolczak, Sophie
  organization: Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
– sequence: 2
  givenname: Ashish R
  surname: Deshwar
  fullname: Deshwar, Ashish R
  organization: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada
– sequence: 3
  givenname: Evangelina
  surname: Aristegui
  fullname: Aristegui, Evangelina
  organization: Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
– sequence: 4
  givenname: Binita M
  surname: Kamath
  fullname: Kamath, Binita M
  organization: Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada
– sequence: 5
  givenname: Michael W
  surname: Lawlor
  fullname: Lawlor, Michael W
  organization: Pathology, Medical College of Wisconsin, Milwaukee, United States of America
– sequence: 6
  givenname: Gaia
  surname: Andreoletti
  fullname: Andreoletti, Gaia
  organization: Astellas Gene Therapies, San Francisco, United States of America
– sequence: 7
  givenname: Jonathan R
  surname: Volpatti
  fullname: Volpatti, Jonathan R
  organization: Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada
– sequence: 8
  givenname: Jillian L
  surname: Ellis
  fullname: Ellis, Jillian L
  organization: Division of Gastroenterology, Hepatology and Nutrition and Division of Deve, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
– sequence: 9
  givenname: Chunyue
  surname: Yin
  fullname: Yin, Chunyue
  organization: Division of Gastroenterology, Hepatology and Nutrition and Division of Deve, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
– sequence: 10
  givenname: James J
  surname: Dowling
  fullname: Dowling, James J
  organization: The Hospital for Sick Children, Toronto, Canada
BackLink https://www.ncbi.nlm.nih.gov/pubmed/37490339$$D View this record in MEDLINE/PubMed
BookMark eNqNk1tv0zAUgCM0xC7wwB9AkZAQPGT4lth5mqaKQVHRJG7am-XYx62LE5c4mdZ_j8tGaVEfkB9sHX_n8-34NDvqQgdZ9hyjc4w5eftxMsVVRXj5KDvBZSkKQag42hkfZ6cxLhHCjJXsSXZMOasRpfVJdjMLMebB5p-GFudajRFirhfBQxzU4HTu3S30uXERVITcdbnK22DAb3JuCu-6H2Dydh2GsRm96jfDlRoW66fZY6t8hGcP_Vn27erd18mHYnb9fjq5nBWaYzYUrFKsIsjoxlQESiI0xawUUAE1FlHgglmOlOVQaUIbUlkNtlEUW4NUzTk9y6b3XhPUUq5616p-LYNy8ncg9HOp-nQQD1I11mClG2rrmmmGhLC2obxG2AhLSJ1cF_eu1di0YDR0Q6_8nnR_pnMLOQ-3EqMSJVGZDK8fDH34OaY7lK2LGrxXHYQxSiIYYWVFCE3oy3_QZRj7Lt1VoniJaS3K6i81V-kErrMhLaw3UnnJKyGSjbBEFQeoOXSQdplqxboU3uPPD_CpGWidPpjwZi8hMQPcDfNUL1FOv3z-f_b6-z77aoddgPLDIgY_Di508aBU96lge7DbV8FIbj6B3H6CxL7YfcYt-afq6S8kQP7_
CitedBy_id crossref_primary_10_3389_fcvm_2024_1364604
crossref_primary_10_1016_S1474_4422_23_00416_7
crossref_primary_10_3390_gastroent15010011
crossref_primary_10_1016_S1474_4422_23_00313_7
crossref_primary_10_14309_crj_0000000000001240
Cites_doi 10.1038/nature16516
10.1038/s41467-018-07058-4
10.3389/neuro.04.021.2009
10.1038/ncomms15661
10.1242/jcs.01217
10.1172/JCI86841
10.3389/fmed.2021.574047
10.3233/JND-210712
10.1091/mbc.e08-04-0367
10.3233/JND-180309
10.1186/1750-1172-3-26
10.1016/j.sbi.2005.10.016
10.1016/j.mod.2009.07.002
10.1089/hum.2020.217
10.1002/cphy.c120021
10.1002/hep.1840120523
10.3389/fendo.2018.00001
10.1073/pnas.212498399
10.4254/wjh.v9.i8.418
10.1016/j.ydbio.2011.09.010
10.1016/j.intimp.2020.107328
10.1053/j.gastro.2015.08.034
10.1002/cphy.c120027
10.1002/hep.20090
10.1186/s12964-015-0102-1
10.1111/tra.12119
10.1126/scitranslmed.3007523
10.1242/dmm.038174
10.1212/WNL.0000000000004415
10.1038/s41467-018-07057-5
10.1016/j.nmd.2021.08.003
10.1007/s40139-017-0141-y
10.1371/journal.pgen.1000372
10.1016/j.ydbio.2014.08.025
10.1002/mus.23463
10.1083/jcb.200105138
10.1016/j.jhep.2017.01.001
10.1080/21678707.2018.1443807
10.1038/3034
10.1073/pnas.160255697
10.1002/hep.29632
ContentType Journal Article
Copyright COPYRIGHT 2023 American Society for Clinical Investigation
Copyright American Society for Clinical Investigation Sep 2023
2023 Karolczak et al. 2023 Karolczak et al.
Copyright_xml – notice: COPYRIGHT 2023 American Society for Clinical Investigation
– notice: Copyright American Society for Clinical Investigation Sep 2023
– notice: 2023 Karolczak et al. 2023 Karolczak et al.
DBID NPM
AAYXX
CITATION
IOV
ISR
3V.
7RV
7X7
7XB
88A
88E
8AO
8FE
8FH
8FI
8FJ
8FK
ABUWG
AFKRA
AZQEC
BBNVY
BEC
BENPR
BHPHI
CCPQU
DWQXO
FYUFA
GHDGH
GNUQQ
HCIFZ
K9.
KB0
LK8
M0S
M1P
M7P
NAPCQ
PQEST
PQQKQ
PQUKI
S0X
7X8
5PM
DOA
DOI 10.1172/JCI166275
DatabaseName PubMed
CrossRef
Gale In Context: Opposing Viewpoints database
Science in Context
ProQuest Central (Corporate)
ProQuest Nursing and Allied Health Journals
Health & Medical Collection
ProQuest Central (purchase pre-March 2016)
Biology Database (Alumni Edition)
Medical Database (Alumni Edition)
ProQuest Pharma Collection
ProQuest SciTech Collection
ProQuest Natural Science Collection
Hospital Premium Collection
Hospital Premium Collection (Alumni Edition)
ProQuest Central (Alumni) (purchase pre-March 2016)
ProQuest Central (Alumni)
ProQuest Central
ProQuest Central Essentials
Biological Science Collection
eLibrary
ProQuest Central
Natural Science Collection
ProQuest One Community College
ProQuest Central Korea
Health Research Premium Collection
Health Research Premium Collection (Alumni)
ProQuest Central Student
SciTech Premium Collection
ProQuest Health & Medical Complete (Alumni)
Nursing & Allied Health Database (Alumni Edition)
Biological Sciences
Health & Medical Collection (Alumni Edition)
Medical Database
Biological Science Database
Nursing & Allied Health Premium
ProQuest One Academic Eastern Edition (DO NOT USE)
ProQuest One Academic
ProQuest One Academic UKI Edition
SIRS Editorial
MEDLINE - Academic
PubMed Central (Full Participant titles)
DOAJ Directory of Open Access Journals
DatabaseTitle PubMed
CrossRef
ProQuest Central Student
ProQuest Central Essentials
SIRS Editorial
elibrary
ProQuest Health & Medical Complete (Alumni)
ProQuest Central (Alumni Edition)
SciTech Premium Collection
ProQuest One Community College
ProQuest Natural Science Collection
ProQuest Pharma Collection
ProQuest Biology Journals (Alumni Edition)
ProQuest Central
Health Research Premium Collection
Health and Medicine Complete (Alumni Edition)
Natural Science Collection
ProQuest Central Korea
Biological Science Collection
ProQuest Medical Library (Alumni)
ProQuest Biological Science Collection
ProQuest One Academic Eastern Edition
ProQuest Nursing & Allied Health Source
ProQuest Hospital Collection
Health Research Premium Collection (Alumni)
Biological Science Database
ProQuest SciTech Collection
ProQuest Hospital Collection (Alumni)
Nursing & Allied Health Premium
ProQuest Health & Medical Complete
ProQuest Medical Library
ProQuest One Academic UKI Edition
ProQuest Nursing & Allied Health Source (Alumni)
ProQuest One Academic
ProQuest Central (Alumni)
MEDLINE - Academic
DatabaseTitleList PubMed



ProQuest Central Student
MEDLINE - Academic
Database_xml – sequence: 1
  dbid: DOA
  name: DOAJ Directory of Open Access Journals
  url: https://www.doaj.org/
  sourceTypes: Open Website
– sequence: 2
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 3
  dbid: BENPR
  name: ProQuest Central
  url: https://www.proquest.com/central
  sourceTypes: Aggregation Database
DeliveryMethod fulltext_linktorsrc
Discipline Medicine
EISSN 1558-8238
EndPage 13
ExternalDocumentID oai_doaj_org_article_abfd1acb3f994c4088ffb37901d8f229
A768824524
10_1172_JCI166275
37490339
Genre Journal Article
GeographicLocations Canada
GeographicLocations_xml – name: Canada
GrantInformation_xml – fundername: NIDDK NIH HHS
  grantid: P30 DK078392
– fundername: NIDDK NIH HHS
  grantid: R01 DK117266
– fundername: ;
  grantid: N/A
GroupedDBID ---
-~X
.55
.XZ
08G
08P
29K
354
36B
3V.
5GY
5RE
5RS
7RV
7X7
88A
88E
8AO
8F7
8FE
8FH
8FI
8FJ
8R4
8R5
AAWTL
ABOCM
ABPMR
ABUWG
ACGFO
ACIHN
ACNCT
ACPRK
ADBBV
AEAQA
AENEX
AFCHL
AFKRA
AHMBA
ALIPV
ALMA_UNASSIGNED_HOLDINGS
AOIJS
ASPBG
AVWKF
AZFZN
BAWUL
BBNVY
BCU
BEC
BENPR
BHPHI
BKEYQ
BLC
BPHCQ
BVXVI
CCPQU
CS3
D-I
DIK
DU5
E3Z
EBS
EJD
EMB
EX3
F5P
FRP
FYUFA
GROUPED_DOAJ
GX1
HCIFZ
HMCUK
HYE
IAO
IEA
IHR
IHW
INH
INR
IOF
IOV
IPO
ISR
ITC
KQ8
L7B
LK8
M0L
M1P
M5~
M7P
NAPCQ
NPM
OBH
OCB
ODZKP
OFXIZ
OGEVE
OHH
OK1
OVD
OVIDX
P2P
P6G
PQQKQ
PROAC
PSQYO
Q2X
RPM
S0X
SJFOW
SV3
TEORI
TR2
TVE
UKHRP
VVN
W2D
WH7
WOQ
WOW
X7M
XSB
YFH
YHG
YKV
YOC
ZY1
~H1
AAYXX
CITATION
7XB
8FK
AZQEC
DWQXO
GNUQQ
K9.
PQEST
PQUKI
7X8
5PM
ID FETCH-LOGICAL-c714t-46a4620dcbd62e528c31458e6e3df03e784f70af7e6c23b26fcefba31fd0a9773
IEDL.DBID RPM
ISSN 1558-8238
0021-9738
IngestDate Tue Oct 22 15:15:54 EDT 2024
Tue Sep 17 21:29:36 EDT 2024
Sat Oct 26 04:10:27 EDT 2024
Thu Dec 05 18:22:34 EST 2024
Tue Nov 19 21:43:26 EST 2024
Thu Nov 14 21:29:39 EST 2024
Wed Nov 13 00:23:24 EST 2024
Sat Sep 28 21:29:23 EDT 2024
Sat Sep 28 21:11:40 EDT 2024
Tue Aug 20 22:00:38 EDT 2024
Fri Dec 06 03:06:10 EST 2024
Wed Oct 16 00:39:48 EDT 2024
IsDoiOpenAccess true
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 18
Keywords Muscle Biology
Hepatology
Monogenic diseases
Language English
License http://creativecommons.org/licenses/by/4.0
This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-c714t-46a4620dcbd62e528c31458e6e3df03e784f70af7e6c23b26fcefba31fd0a9773
Notes ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Authorship note: SK and ARD contributed equally to this work.
ORCID 0000-0003-1764-1149
0000-0002-3984-4169
0000-0003-0731-3950
0000-0002-0452-0009
OpenAccessLink https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503795/
PMID 37490339
PQID 2875139856
PQPubID 42166
PageCount 13
ParticipantIDs doaj_primary_oai_doaj_org_article_abfd1acb3f994c4088ffb37901d8f229
pubmedcentral_primary_oai_pubmedcentral_nih_gov_10503795
proquest_miscellaneous_2842456223
proquest_journals_2875139856
gale_infotracmisc_A768824524
gale_infotracgeneralonefile_A768824524
gale_infotracacademiconefile_A768824524
gale_incontextgauss_ISR_A768824524
gale_incontextgauss_IOV_A768824524
gale_healthsolutions_A768824524
crossref_primary_10_1172_JCI166275
pubmed_primary_37490339
PublicationCentury 2000
PublicationDate 2023-09-15
PublicationDateYYYYMMDD 2023-09-15
PublicationDate_xml – month: 09
  year: 2023
  text: 2023-09-15
  day: 15
PublicationDecade 2020
PublicationPlace United States
PublicationPlace_xml – name: United States
– name: Ann Arbor
PublicationTitle The Journal of clinical investigation
PublicationTitleAlternate J Clin Invest
PublicationYear 2023
Publisher American Society for Clinical Investigation
Publisher_xml – sequence: 0
  name: American Society for Clinical Investigation
– name: American Society for Clinical Investigation
References B20
B42
B21
B22
B44
B23
B45
B24
B25
B26
B27
B28
B29
B30
Shieh (B7) 2020; 94
B31
B10
B32
B33
B12
B34
B13
B35
B14
B36
B15
B37
B16
B38
B17
B39
B18
B19
Li (B43) 2021; 10
B1
B2
B3
B4
B5
B6
B8
B9
Amoasii (B11) 2012; 362
B40
B41
References_xml – ident: B26
  doi: 10.1038/nature16516
– ident: B36
  doi: 10.1038/s41467-018-07058-4
– ident: B44
  doi: 10.3389/neuro.04.021.2009
– ident: B34
  doi: 10.1038/ncomms15661
– ident: B41
  doi: 10.1242/jcs.01217
– ident: B16
  doi: 10.1172/JCI86841
– ident: B45
  doi: 10.3389/fmed.2021.574047
– ident: B8
  doi: 10.3233/JND-210712
– ident: B39
  doi: 10.1091/mbc.e08-04-0367
– ident: B35
  doi: 10.3233/JND-180309
– ident: B2
  doi: 10.1186/1750-1172-3-26
– ident: B10
  doi: 10.1016/j.sbi.2005.10.016
– ident: B24
  doi: 10.1016/j.mod.2009.07.002
– ident: B6
  doi: 10.1089/hum.2020.217
– ident: B19
  doi: 10.1002/cphy.c120021
– ident: B22
  doi: 10.1002/hep.1840120523
– ident: B28
  doi: 10.3389/fendo.2018.00001
– ident: B14
  doi: 10.1073/pnas.212498399
– ident: B29
  doi: 10.4254/wjh.v9.i8.418
– volume: 10
  start-page: 1
  issue: 2
  year: 2021
  ident: B43
  article-title: A Link between intrahepatic cholestasis and genetic variations in intracellular trafficking regulators
  publication-title: Biology (Basel)
  contributor:
    fullname: Li
– ident: B21
  doi: 10.1016/j.ydbio.2011.09.010
– ident: B30
  doi: 10.1016/j.intimp.2020.107328
– ident: B20
  doi: 10.1053/j.gastro.2015.08.034
– ident: B27
  doi: 10.1002/cphy.c120027
– ident: B31
  doi: 10.1002/hep.20090
– ident: B37
  doi: 10.1186/s12964-015-0102-1
– ident: B38
  doi: 10.1111/tra.12119
– ident: B5
  doi: 10.1126/scitranslmed.3007523
– ident: B25
  doi: 10.1242/dmm.038174
– ident: B3
  doi: 10.1212/WNL.0000000000004415
– ident: B33
  doi: 10.1038/s41467-018-07057-5
– ident: B32
  doi: 10.1016/j.nmd.2021.08.003
– volume: 94
  issue: 15 suppl
  year: 2020
  ident: B7
  article-title: ASPIRO gene therapy trial In X-Linked Myotubular Myopathy (XLMTM): update on preliminary safety and efficacy findings up to 72 weeks post-treatment (1053)
  publication-title: Neurology
  contributor:
    fullname: Shieh
– ident: B18
  doi: 10.1007/s40139-017-0141-y
– ident: B1
  doi: 10.1371/journal.pgen.1000372
– volume: 362
  start-page: 209
  year: 2012
  ident: B11
  article-title: Myotubularin phosphoinositide phosphatases in human diseases
  publication-title: Curr Top Microbiol Immunol
  contributor:
    fullname: Amoasii
– ident: B17
– ident: B23
  doi: 10.1016/j.ydbio.2014.08.025
– ident: B15
  doi: 10.1002/mus.23463
– ident: B40
  doi: 10.1083/jcb.200105138
– ident: B42
  doi: 10.1016/j.jhep.2017.01.001
– ident: B4
  doi: 10.1080/21678707.2018.1443807
– ident: B12
  doi: 10.1038/3034
– ident: B9
  doi: 10.1073/pnas.160255697
– ident: B13
  doi: 10.1002/hep.29632
SSID ssj0014454
Score 2.5158956
Snippet X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, though...
X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although...
X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although...
SourceID doaj
pubmedcentral
proquest
gale
crossref
pubmed
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
StartPage 1
SubjectTerms Acids
Animal models
Bile
Bile ducts
Biomedical research
Causes of
Complications and side effects
Congenital diseases
Danio rerio
Dynamin
Endosomes
Gallbladder
Gallbladder diseases
Gene therapy
Genetic aspects
Genotype & phenotype
Hepatology
Lipids
Liver diseases
Localization
MTM1 gene
Muscle biology
Mutation
Myopathy
Neuromuscular diseases
Ostomy
Pathology
Phenotypes
Protein transport
Protein turnover
Proteins
Zebrafish
SummonAdditionalLinks – databaseName: DOAJ Directory of Open Access Journals
  dbid: DOA
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrV1Lb9QwELZQD4gL4k2ggEEITlETP5NjqajaigUJKNpbZDt2uxJNEJs99N8zk3ijtUCCA5fVav1FG814PDOamc-EvDYQBMhC2RyiafhADkgLXiuXGmITsBBTKxxOXnxUJ-fibCmXO1d9YU_YRA88Ce7A2NCWxlke6lo4AUYRguUa3FhbBcam0b2CbZOpWD8QQorIIwQe-uDs6LQcmc4T7zOS9P9-FO_4orRPcsfxHN8ht2PESA-nN71LbvjuHrm5iDXx-2T5Af6J9oEuhquSOrNZ-zXFQ83jsNDK0e_YekFjJYauOmroeP8NPrPMsYLrW3p13Q8biz2p-BXvKb5-QM6P3389OsnjfQm506UYcqGMUKxonW0V85JVjpdCVl553oaCe12JoAsTtFeOcctUcD5Yw8vQFgbiQP6Q7HV95x8T6mrJZFA1txVkgLI2vIXAw_qaK1f5Vmfk1VaOzY-JFqMZ0wnNmlnYGXmHEp4ByGQ9_gD6baJ-m7_pNyMvUD_NNBY622NzCHlShWVjAe8yIpDNosN2mQuQ9Lo5_fTtH0BfPiegtxEUelC4M3FEAWSCLFkJ8k2CvJg4wv8E3E-AYLwuXd5uuyYeHusGklgJgXklVUZezsv4JDbEdb7fIGYsWUNwl5FH0y6d5cy1qAvOQXRVsn8TRaQr3epypBYvkR5I1_LJ_1DdU3IL7J1jd00p98ne8HPjn0EIN9jno7X-Au2gQ5U
  priority: 102
  providerName: Directory of Open Access Journals
– databaseName: Health & Medical Collection
  dbid: 7X7
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV1Nb9QwELWgSIgL4ruBFgxCcIqaxLEdn6pSUbUVCxJQlFtkO_ayEk1Kkz303zOTeEMjEOISreKJNhp7Zt5kxs-EvNYAAngiTAxoGi7IAWkgasVcAjYBC9FK4ObkxUdxfJaflrwMH9y60Fa58YmDo65bi9_I9wDZc0ArBRf7Fz9jPDUKq6vhCI2b5FaaQSiH9SzLKeGCXIEHFuY0VpIVgVkIYvbe6eFJOnCfz-LRQNv_p3O-Fp3mnZPXQtHRPXI3YEh6ME76fXLDNQ_I7UWokj8k5Qf4J9p6uujPU2r1unMdRTfncPvQytIf2IxBQ22Grhqq6XAiDj5TxljTdTU9v2r7tcEuVfyJJxdfPSJnR--_Hh7H4QSF2Mo07-Nc6FxkSW1NLTLHs8KyNOeFE47VPmFOFrmXifbSCZsxkwlvnTeapb5ONCBD9phsNW3jtgm1imfcC8VMATkhV5rVAEWMU0zYwtUyIq82eqwuRqKMakgwZFZNyo7IO9TwJIDc1sON9nJZBVOptPF1qq1hXqnc5uAGvTdMAnCpC59lKiIvcH6qcaPoZKHVAWROBRaSc3iXQQL5LRpsoFmCprvq5NO3_xD68nkm9DYI-RYm3OqwaQF0grxZM8k3M8nlyBr-N8GdmSCYs50Pb5ZdFdxJV_1e_BF5OQ3jk9gi17h2jTJDERvgXkSejKt00jOTuUoYA9UVs_U7m4j5SLP6PpCNp0gYJBV_-u_3ekbugG0z7KRJ-Q7Z6i_XbhfgWm-eDzb5C-n4PB0
  priority: 102
  providerName: ProQuest
Title Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy
URI https://www.ncbi.nlm.nih.gov/pubmed/37490339
https://www.proquest.com/docview/2875139856
https://www.proquest.com/docview/2842456223
https://pubmed.ncbi.nlm.nih.gov/PMC10503795
https://doaj.org/article/abfd1acb3f994c4088ffb37901d8f229
Volume 133
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3db9MwELe2IU17QeM7bBSDEDxlTeKPJI9b2bQOOqbBUN8i27FLpTWZ1vZh_z13blI1ggfES9XWP6vR2ee76939TMgHBU6AiKQOwZuGF-SA1GC1QpGCbwIaonKJzcmjS3l-wy_GYrxFZNsL44v2jZ4eVbezo2r6y9dW3s1Mv60T61-NBjGSmKS56G-TbbC_bYze5A44Fw33chzmKcsaPiGw1P2LwTD2jOd7ZJelPI8YXhK-YZA8b_-fp_OGeeqWTm7YorN98rhxIunx6mGfkC1bPSW7oyZN_oyMv8Iv0drR0WIWU6OWczuneM5Z7B-aGnqL1Ri0Sc7QaUUV9Vfi4JxxiEldW9LZQ71YaixTxbd4dfHDc3JzdvpjcB42VyiEJo35IuRScZlEpdGlTKxIMsNiLjIrLStdxGyacZdGyqVWmoTpRDpjnVYsdmWkwDVkL8hOVVf2FaEmF4lwMmc6g6BQ5IqV4ItomzNpMlumAXnfyrG4WzFlFD7CSJNiLfeAnKCE1wAkt_Zf1PeTolniQmlXxspo5vKcGw7noHMa1juKy8wlSR6Qt7g-xapTdK2ixTGEThlmkjk8i0cgwUWFFTQTkPS8GH77-Q-g79cd0KcG5GpYcKOargWQCRJndZAfO8jJijb8b8DDDhD02XSH221XNOfJvIC4VoCvngkZkHfrYZyJNXKVrZeI8Vls8PcC8nK1S9dybjd7QLLO_u0sRHcElM-zjbfK9vr_px6QPVB8hmU2sTgkO4v7pX0DvtxC90CBx2mPPDo5vby6hk-fh196_n-Rnlfq36JHSdY
link.rule.ids 230,314,727,780,784,864,885,2102,12056,21388,27924,27925,31719,31720,33744,33745,43310,43805,53791,53793,73745,74302
linkProvider National Library of Medicine
linkToHtml http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV3db9MwELegk4AXxDeFwQxC8BQtiT-SPKFt2tSOtqCxob5ZtmOXSluyre3D_nvuUjcsAiFeoiq-qNHZd_dz7vw7Qj5oAAEiliYCNA0X5IA0ELUikQE2AQvRhcTDyeOJHJzx46mYhg9ui1BWufGJjaMua4vfyHcB2QtAK7mQny-vIuwahdnV0ELjLtlC5nTRI1v7h5NvJ20egXMReJiTqMhYHriFIGrvHh8Mk4b9vBORGuL-P93zrfjUrZ28FYyOHpGHAUXSvfW0PyZ3XPWE3BuHPPlTMh3BP9Ha0_HyIqFWrxZuQdHROTxANLf0HMsxaMjO0HlFNW164uAz0wizuq6kFzf1cmWwThV_Yu_im2fk7Ojw9GAQhR4Kkc0Svoy41FymcWlNKVMn0tyyhIvcScdKHzOX5dxnsfaZkzZlJpXeOm80S3wZa8CG7DnpVXXlXhJqC5EKLwtmctgVikKzEsCIcQWTNndl1ifvN3pUl2uqDNVsMbJUtcruk33UcCuA7NbNjfp6poKxKG18mWhrmC8Kbjk4Qu8NywC6lLlP06JPdnB-1PqoaGujag_2Tjmmkjm8SyOBDBcVltDMQNMLNfz64z-Evp90hD4FIV_DhFsdji2ATpA5qyP5sSM5W_OG_01wuyMIBm27w5tlp4JDWajfy79P3rXD-CQWyVWuXqFMk8YGwNcnL9artNUzy3gRMwaqyzvrtzMR3ZFq_rOhG0-QMigrxKt_v9cOuT84HY_UaDj58po8AEtnWFeTiG3SW16v3BsAb0vzNljoL0VzQHM
linkToPdf http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV3db9MwELegkyZeEN8rDGYQgqeoSfyR-AltY9U61jINhvoW2Y5dKrFkrO3D_nvuUjcsAiFeqqi-KNH5Pn7OnX8m5K0GECBiaSJA0_CDHJAGslYkMsAm4CFaSdycPJ7I4wt-MhXT0P-0CG2Vm5jYBOqytviNfADIXgBayYUc-NAWcfZx-OHqZ4QnSGGlNRyncZdsQVaM0x7ZOjianJ23NQXOReBkTiKVsTzwDEEGH5wcjpKGCb2TnRoS_z9D9a1c1e2jvJWYhg_I_YAo6f7aBB6SO656RLbHoWb-mExP4Um09nS8vEyo1auFW1AMeg43E80t_YGtGTRUaui8opo25-PgPdMIK7yupJc39XJlsGcVL_Ec45sn5GJ49PXwOArnKUQ2S_gy4lJzmcalNaVMnUhzyxIucicdK33MXJZzn8XaZ07alJlUeuu80SzxZawBJ7KnpFfVldsh1CqRCi8VMzmsEIXSrARgYpxi0uauzPrkzUaPxdWaNqNolhtZWrTK7pMD1HArgEzXzR_19awIjlNo48tEW8O8UtxyCIreG5YBjClzn6aqT_Zwfor1ttHWX4t9WEflWFbm8C6NBLJdVGg3M9D0ohh9_vYfQl_OO0Lvg5CvYcKtDlsYQCfIotWRfNeRnK05xP8muNsRBOe23eGN2RUhuCyK367QJ6_bYbwTG-YqV69QpilpA_jrk2drK231zDKuYsZAdXnHfjsT0R2p5t8b6vEE6YMyJZ7_-732yDY4Z3E6mnx6Qe6B0zNssUnELuktr1fuJeC4pXkVHPQXcKtEoA
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Loss+of+Mtm1+causes+cholestatic+liver+disease+in+a+model+of+X-linked+myotubular+myopathy&rft.jtitle=The+Journal+of+clinical+investigation&rft.au=Sophie+Karolczak&rft.au=Ashish+R.+Deshwar&rft.au=Evangelina+Aristegui&rft.au=Binita+M.+Kamath&rft.date=2023-09-15&rft.pub=American+Society+for+Clinical+Investigation&rft.eissn=1558-8238&rft.volume=133&rft.issue=18&rft_id=info:doi/10.1172%2FJCI166275&rft.externalDBID=DOA&rft.externalDocID=oai_doaj_org_article_abfd1acb3f994c4088ffb37901d8f229
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1558-8238&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1558-8238&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1558-8238&client=summon