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Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin
Obscurins are cytoskeletal proteins with structural and regulatory roles encoded by OBSCN. Mutations in OBSCN are associated with the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Specifically, the R4344Q mutation present in immunoglobulin domain 58 (Ig58) was th...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462502/ https://www.ncbi.nlm.nih.gov/pubmed/28630914 http://dx.doi.org/10.1126/sciadv.1603081 |
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author | Hu, Li-Yen R. Ackermann, Maegen A. Hecker, Peter A. Prosser, Benjamin L. King, Brendan O’Connell, Kelly A. Grogan, Alyssa Meyer, Logan C. Berndsen, Christopher E. Wright, Nathan T. Jonathan Lederer, W. Kontrogianni-Konstantopoulos, Aikaterini |
author_facet | Hu, Li-Yen R. Ackermann, Maegen A. Hecker, Peter A. Prosser, Benjamin L. King, Brendan O’Connell, Kelly A. Grogan, Alyssa Meyer, Logan C. Berndsen, Christopher E. Wright, Nathan T. Jonathan Lederer, W. Kontrogianni-Konstantopoulos, Aikaterini |
author_sort | Hu, Li-Yen R. |
collection | PubMed |
description | Obscurins are cytoskeletal proteins with structural and regulatory roles encoded by OBSCN. Mutations in OBSCN are associated with the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Specifically, the R4344Q mutation present in immunoglobulin domain 58 (Ig58) was the first to be linked with the development of HCM. To assess the effects of R4344Q in vivo, we generated the respective knock-in mouse model. Mutant obscurins are expressed and incorporated normally into sarcomeres. The expression patterns of sarcomeric and Ca(2+)-cycling proteins are unaltered in sedentary 1-year-old knock-in myocardia, with the exception of sarco/endoplasmic reticulum Ca(2+) adenosine triphosphatase 2 (SERCA2) and pentameric phospholamban whose levels are significantly increased and decreased, respectively. Isolated cardiomyocytes from 1-year-old knock-in hearts exhibit increased Ca(2+)-transients and Ca(2+)-load in the sarcoplasmic reticulum and faster contractility kinetics. Moreover, sedentary 1-year-old knock-in animals develop tachycardia accompanied by premature ventricular contractions, whereas 2-month-old knock-in animals subjected to pressure overload develop a DCM-like phenotype. Structural analysis revealed that the R4344Q mutation alters the distribution of electrostatic charges over the Ig58 surface, thus interfering with its binding capabilities. Consistent with this, wild-type Ig58 interacts with phospholamban modestly, and this interaction is markedly enhanced in the presence of R4344Q. Together, our studies demonstrate that under sedentary conditions, the R4344Q mutation results in Ca(2+) deregulation and spontaneous arrhythmia, whereas in the presence of chronic, pathological stress, it leads to cardiac remodeling and dilation. We postulate that enhanced binding between mutant obscurins and phospholamban leads to SERCA2 disinhibition, which may underlie the observed pathological alterations. |
format | Online Article Text |
id | pubmed-5462502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54625022017-06-19 Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin Hu, Li-Yen R. Ackermann, Maegen A. Hecker, Peter A. Prosser, Benjamin L. King, Brendan O’Connell, Kelly A. Grogan, Alyssa Meyer, Logan C. Berndsen, Christopher E. Wright, Nathan T. Jonathan Lederer, W. Kontrogianni-Konstantopoulos, Aikaterini Sci Adv Research Articles Obscurins are cytoskeletal proteins with structural and regulatory roles encoded by OBSCN. Mutations in OBSCN are associated with the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Specifically, the R4344Q mutation present in immunoglobulin domain 58 (Ig58) was the first to be linked with the development of HCM. To assess the effects of R4344Q in vivo, we generated the respective knock-in mouse model. Mutant obscurins are expressed and incorporated normally into sarcomeres. The expression patterns of sarcomeric and Ca(2+)-cycling proteins are unaltered in sedentary 1-year-old knock-in myocardia, with the exception of sarco/endoplasmic reticulum Ca(2+) adenosine triphosphatase 2 (SERCA2) and pentameric phospholamban whose levels are significantly increased and decreased, respectively. Isolated cardiomyocytes from 1-year-old knock-in hearts exhibit increased Ca(2+)-transients and Ca(2+)-load in the sarcoplasmic reticulum and faster contractility kinetics. Moreover, sedentary 1-year-old knock-in animals develop tachycardia accompanied by premature ventricular contractions, whereas 2-month-old knock-in animals subjected to pressure overload develop a DCM-like phenotype. Structural analysis revealed that the R4344Q mutation alters the distribution of electrostatic charges over the Ig58 surface, thus interfering with its binding capabilities. Consistent with this, wild-type Ig58 interacts with phospholamban modestly, and this interaction is markedly enhanced in the presence of R4344Q. Together, our studies demonstrate that under sedentary conditions, the R4344Q mutation results in Ca(2+) deregulation and spontaneous arrhythmia, whereas in the presence of chronic, pathological stress, it leads to cardiac remodeling and dilation. We postulate that enhanced binding between mutant obscurins and phospholamban leads to SERCA2 disinhibition, which may underlie the observed pathological alterations. American Association for the Advancement of Science 2017-06-07 /pmc/articles/PMC5462502/ /pubmed/28630914 http://dx.doi.org/10.1126/sciadv.1603081 Text en Copyright © 2017, The Authors http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Hu, Li-Yen R. Ackermann, Maegen A. Hecker, Peter A. Prosser, Benjamin L. King, Brendan O’Connell, Kelly A. Grogan, Alyssa Meyer, Logan C. Berndsen, Christopher E. Wright, Nathan T. Jonathan Lederer, W. Kontrogianni-Konstantopoulos, Aikaterini Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
title | Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
title_full | Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
title_fullStr | Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
title_full_unstemmed | Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
title_short | Deregulated Ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
title_sort | deregulated ca(2+) cycling underlies the development of arrhythmia and heart disease due to mutant obscurin |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462502/ https://www.ncbi.nlm.nih.gov/pubmed/28630914 http://dx.doi.org/10.1126/sciadv.1603081 |
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