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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9323361 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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