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Compound loss of muscleblind-like function in myotonic dystrophy

Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing fact...

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Autores principales: Lee, Kuang-Yung, Li, Moyi, Manchanda, Mini, Batra, Ranjan, Charizanis, Konstantinos, Mohan, Apoorva, Warren, Sonisha A, Chamberlain, Christopher M, Finn, Dustin, Hong, Hannah, Ashraf, Hassan, Kasahara, Hideko, Ranum, Laura P W, Swanson, Maurice S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914532/
https://www.ncbi.nlm.nih.gov/pubmed/24293317
http://dx.doi.org/10.1002/emmm.201303275
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author Lee, Kuang-Yung
Li, Moyi
Manchanda, Mini
Batra, Ranjan
Charizanis, Konstantinos
Mohan, Apoorva
Warren, Sonisha A
Chamberlain, Christopher M
Finn, Dustin
Hong, Hannah
Ashraf, Hassan
Kasahara, Hideko
Ranum, Laura P W
Swanson, Maurice S
author_facet Lee, Kuang-Yung
Li, Moyi
Manchanda, Mini
Batra, Ranjan
Charizanis, Konstantinos
Mohan, Apoorva
Warren, Sonisha A
Chamberlain, Christopher M
Finn, Dustin
Hong, Hannah
Ashraf, Hassan
Kasahara, Hideko
Ranum, Laura P W
Swanson, Maurice S
author_sort Lee, Kuang-Yung
collection PubMed
description Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1(−/−); Mbnl2(−/−) double knockouts (DKOs) are embryonic lethal, Mbnl1(−/−); Mbnl2(+/−) mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1(−/−) knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.
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spelling pubmed-39145322014-02-10 Compound loss of muscleblind-like function in myotonic dystrophy Lee, Kuang-Yung Li, Moyi Manchanda, Mini Batra, Ranjan Charizanis, Konstantinos Mohan, Apoorva Warren, Sonisha A Chamberlain, Christopher M Finn, Dustin Hong, Hannah Ashraf, Hassan Kasahara, Hideko Ranum, Laura P W Swanson, Maurice S EMBO Mol Med Research Articles Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1(−/−); Mbnl2(−/−) double knockouts (DKOs) are embryonic lethal, Mbnl1(−/−); Mbnl2(+/−) mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1(−/−) knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease. John Wiley and Sons 2013-12 2013-10-08 /pmc/articles/PMC3914532/ /pubmed/24293317 http://dx.doi.org/10.1002/emmm.201303275 Text en © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Lee, Kuang-Yung
Li, Moyi
Manchanda, Mini
Batra, Ranjan
Charizanis, Konstantinos
Mohan, Apoorva
Warren, Sonisha A
Chamberlain, Christopher M
Finn, Dustin
Hong, Hannah
Ashraf, Hassan
Kasahara, Hideko
Ranum, Laura P W
Swanson, Maurice S
Compound loss of muscleblind-like function in myotonic dystrophy
title Compound loss of muscleblind-like function in myotonic dystrophy
title_full Compound loss of muscleblind-like function in myotonic dystrophy
title_fullStr Compound loss of muscleblind-like function in myotonic dystrophy
title_full_unstemmed Compound loss of muscleblind-like function in myotonic dystrophy
title_short Compound loss of muscleblind-like function in myotonic dystrophy
title_sort compound loss of muscleblind-like function in myotonic dystrophy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914532/
https://www.ncbi.nlm.nih.gov/pubmed/24293317
http://dx.doi.org/10.1002/emmm.201303275
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