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Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling

Background: Mutations in the Lamin A/C (LMNA) gene are responsible for about 6% of all familial dilated cardiomyopathy (DCM) cases which tend to present at a young age and follow a fulminant course. Methods: We report a 47-year-old DCM patient with severely impaired left ventricular ejection fractio...

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Autores principales: Neupane, Balram, Pradhan, Kabita, Ortega-Ramirez, Audrey Magdalena, Aidery, Parwez, Kucikas, Vytautas, Marks, Matthias, van Zandvoort, Marc A. M. J., Klingel, Karin, Witte, Klaus K., Gründer, Stefan, Marx, Nikolaus, Gramlich, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323361/
https://www.ncbi.nlm.nih.gov/pubmed/35887646
http://dx.doi.org/10.3390/jpm12071149
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author Neupane, Balram
Pradhan, Kabita
Ortega-Ramirez, Audrey Magdalena
Aidery, Parwez
Kucikas, Vytautas
Marks, Matthias
van Zandvoort, Marc A. M. J.
Klingel, Karin
Witte, Klaus K.
Gründer, Stefan
Marx, Nikolaus
Gramlich, Michael
author_facet Neupane, Balram
Pradhan, Kabita
Ortega-Ramirez, Audrey Magdalena
Aidery, Parwez
Kucikas, Vytautas
Marks, Matthias
van Zandvoort, Marc A. M. J.
Klingel, Karin
Witte, Klaus K.
Gründer, Stefan
Marx, Nikolaus
Gramlich, Michael
author_sort Neupane, Balram
collection PubMed
description Background: Mutations in the Lamin A/C (LMNA) gene are responsible for about 6% of all familial dilated cardiomyopathy (DCM) cases which tend to present at a young age and follow a fulminant course. Methods: We report a 47-year-old DCM patient with severely impaired left ventricular ejection fraction and NYHA functional class IV despite optimal heart failure treatment. Whole-exome sequencing revealed an LMNA E161K missense mutation as the pathogenetic cause for DCM in this patient. We generated a patient-specific LMNA-knock in (LMNA-KI) in vitro model using mES cells. Results: Beta adrenergic stimulation of cardiomyocytes derived from LMNA-KI mES cells resulted in augmented mTOR signaling and increased dysregulation of action potentials, which could be effectively prevented by the mTOR-inhibitor rapamycin. A cardiac biopsy confirmed strong activation of the mTOR-signaling pathway in the patient. An off-label treatment with oral rapamycin was initiated and resulted in an improvement in left ventricular ejection fraction (27.8% to 44.5%), NT-BNP (8120 ng/L to 2210 ng/L) and NYHA functional class. Conclusion: We have successfully generated the first in vitro model to recapitulate a patient-specific LMNA E161K mutation which leads to a severe form of DCM. The model may serve as a template for individualized and specific treatment of heart failure.
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spelling pubmed-93233612022-07-27 Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling Neupane, Balram Pradhan, Kabita Ortega-Ramirez, Audrey Magdalena Aidery, Parwez Kucikas, Vytautas Marks, Matthias van Zandvoort, Marc A. M. J. Klingel, Karin Witte, Klaus K. Gründer, Stefan Marx, Nikolaus Gramlich, Michael J Pers Med Article Background: Mutations in the Lamin A/C (LMNA) gene are responsible for about 6% of all familial dilated cardiomyopathy (DCM) cases which tend to present at a young age and follow a fulminant course. Methods: We report a 47-year-old DCM patient with severely impaired left ventricular ejection fraction and NYHA functional class IV despite optimal heart failure treatment. Whole-exome sequencing revealed an LMNA E161K missense mutation as the pathogenetic cause for DCM in this patient. We generated a patient-specific LMNA-knock in (LMNA-KI) in vitro model using mES cells. Results: Beta adrenergic stimulation of cardiomyocytes derived from LMNA-KI mES cells resulted in augmented mTOR signaling and increased dysregulation of action potentials, which could be effectively prevented by the mTOR-inhibitor rapamycin. A cardiac biopsy confirmed strong activation of the mTOR-signaling pathway in the patient. An off-label treatment with oral rapamycin was initiated and resulted in an improvement in left ventricular ejection fraction (27.8% to 44.5%), NT-BNP (8120 ng/L to 2210 ng/L) and NYHA functional class. Conclusion: We have successfully generated the first in vitro model to recapitulate a patient-specific LMNA E161K mutation which leads to a severe form of DCM. The model may serve as a template for individualized and specific treatment of heart failure. MDPI 2022-07-15 /pmc/articles/PMC9323361/ /pubmed/35887646 http://dx.doi.org/10.3390/jpm12071149 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Neupane, Balram
Pradhan, Kabita
Ortega-Ramirez, Audrey Magdalena
Aidery, Parwez
Kucikas, Vytautas
Marks, Matthias
van Zandvoort, Marc A. M. J.
Klingel, Karin
Witte, Klaus K.
Gründer, Stefan
Marx, Nikolaus
Gramlich, Michael
Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling
title Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling
title_full Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling
title_fullStr Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling
title_full_unstemmed Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling
title_short Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling
title_sort personalized medicine approach in a dcm patient with lmna mutation reveals dysregulation of mtor signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323361/
https://www.ncbi.nlm.nih.gov/pubmed/35887646
http://dx.doi.org/10.3390/jpm12071149
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