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Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1(ΔE2/ΔE2)) in 129 sv mice results in QRS, QTc widening, bundle block and S...

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Autores principales: Dixon, Donald M., Choi, Jongkyu, El-Ghazali, Ayea, Park, Sun Young, Roos, Kenneth P., Jordan, Maria C., Fishbein, Michael C., Comai, Lucio, Reddy, Sita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356957/
https://www.ncbi.nlm.nih.gov/pubmed/25761764
http://dx.doi.org/10.1038/srep09042
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author Dixon, Donald M.
Choi, Jongkyu
El-Ghazali, Ayea
Park, Sun Young
Roos, Kenneth P.
Jordan, Maria C.
Fishbein, Michael C.
Comai, Lucio
Reddy, Sita
author_facet Dixon, Donald M.
Choi, Jongkyu
El-Ghazali, Ayea
Park, Sun Young
Roos, Kenneth P.
Jordan, Maria C.
Fishbein, Michael C.
Comai, Lucio
Reddy, Sita
author_sort Dixon, Donald M.
collection PubMed
description Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1(ΔE2/ΔE2)) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1(ΔE2/ΔE2) mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tjp1, cell survival, Capn3, Sirt2, Csda, sarcomere and cytoskeleton organization and function, Trim55, Mapt, Pdlim3, Pdlim5, Sorbs1, Sorbs2, Fhod1, Spag9 and structural components of the sarcomere, Myom1, Tnnt2, Zasp. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.
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spelling pubmed-43569572015-03-17 Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms Dixon, Donald M. Choi, Jongkyu El-Ghazali, Ayea Park, Sun Young Roos, Kenneth P. Jordan, Maria C. Fishbein, Michael C. Comai, Lucio Reddy, Sita Sci Rep Article Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1(ΔE2/ΔE2)) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1(ΔE2/ΔE2) mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tjp1, cell survival, Capn3, Sirt2, Csda, sarcomere and cytoskeleton organization and function, Trim55, Mapt, Pdlim3, Pdlim5, Sorbs1, Sorbs2, Fhod1, Spag9 and structural components of the sarcomere, Myom1, Tnnt2, Zasp. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease. Nature Publishing Group 2015-03-12 /pmc/articles/PMC4356957/ /pubmed/25761764 http://dx.doi.org/10.1038/srep09042 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Dixon, Donald M.
Choi, Jongkyu
El-Ghazali, Ayea
Park, Sun Young
Roos, Kenneth P.
Jordan, Maria C.
Fishbein, Michael C.
Comai, Lucio
Reddy, Sita
Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
title Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
title_full Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
title_fullStr Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
title_full_unstemmed Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
title_short Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
title_sort loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356957/
https://www.ncbi.nlm.nih.gov/pubmed/25761764
http://dx.doi.org/10.1038/srep09042
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