{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:18:56Z","timestamp":1789759136522,"version":"4.0.1"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T00:00:00Z","timestamp":1657843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation","award":["GR 3411\/5-1"],"award-info":[{"award-number":["GR 3411\/5-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jpm12071149","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"1149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling"],"prefix":"10.3390","volume":"12","author":[{"given":"Balram","family":"Neupane","sequence":"first","affiliation":[{"name":"Department of Cardiology, Angiology and Critical Care (Medical Clinic 1), University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kabita","family":"Pradhan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Critical Care (Medical Clinic 1), University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey Magdalena","family":"Ortega-Ramirez","sequence":"additional","affiliation":[{"name":"Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parwez","family":"Aidery","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vytautas","family":"Kucikas","sequence":"additional","affiliation":[{"name":"Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1820-1148","authenticated-orcid":false,"given":"Matthias","family":"Marks","sequence":"additional","affiliation":[{"name":"Clinic for Neurology, Section Neurobiological Research, University Hospital RWTH Aachen, 52074 Aachen, Germany"},{"name":"Interdisciplinary Centre for Clinical Research (IZKF) Aachen, Transgenic Service, University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc A. M. J.","family":"van Zandvoort","sequence":"additional","affiliation":[{"name":"Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany"},{"name":"Cardiovascular Research Institute Maastricht (CARIM), Department of Molecular Cell Biology, Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-2498","authenticated-orcid":false,"given":"Karin","family":"Klingel","sequence":"additional","affiliation":[{"name":"Cardiopathology, Institute for Pathology, University Hospital of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7146-7105","authenticated-orcid":false,"given":"Klaus K.","family":"Witte","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Critical Care (Medical Clinic 1), University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-9883","authenticated-orcid":false,"given":"Stefan","family":"Gr\u00fcnder","sequence":"additional","affiliation":[{"name":"Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Marx","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Critical Care (Medical Clinic 1), University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5233-6778","authenticated-orcid":false,"given":"Michael","family":"Gramlich","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Critical Care (Medical Clinic 1), University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163564","DOI":"10.1155\/2015\/163564","article-title":"Pressure overload by transverse aortic constriction induces maladaptive hypertrophy in a titin-truncated mouse model","volume":"2015","author":"Zhou","year":"2015","journal-title":"Biomed. 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