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

B. Neupane, K. Pradhan, A.M. Ortega-Ramirez, P. Aidery, V. Kucikas, M. Marks, M.A.M.J. van Zandvoort, K. Klingel, K.K. Witte, S. Grunder, N. Marx, M. Gramlich*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number1149
Number of pages15
JournalJournal of Personalized Medicine
Volume12
Issue number7
DOIs
Publication statusPublished - 1 Jul 2022

Keywords

  • familial DCM
  • lamin mutation
  • laminopathy
  • mTOR inhibitor
  • individualized therapy
  • EMBRYONIC STEM-CELLS
  • CARDIOMYOCYTE DIFFERENTIATION
  • LAMIN A/C
  • LAMINOPATHIES

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