Dokument: Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues
| Titel: | Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=67474 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20241112-125355-8 | |||||||
| Kollektion: | Publikationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Texte » Artikel, Aufsatz | |||||||
| Medientyp: | Text | |||||||
| Autoren: | Nakhaei-Rad, Saeideh [Autor] Haghighi, Fereshteh [Autor] Bazgir, Farhad [Autor] Dahlmann, Julia [Autor] Busley, Alexandra Viktoria [Autor] Buchholzer, Marcel [Autor] Kleemann, Karolin [Autor] Schänzer, Anne [Autor] Borchardt, Andrea [Autor] Hahn, Andreas [Autor] | |||||||
| Dateien: |
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| Beschreibung: | Noonan syndrome (NS), the most common among RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c.770 C > T missense change. We characterize the molecular, structural, and functional consequences of aberrant RAF1–associated signaling on the cardiac models. Ultrastructural assessment of the sarcomere revealed a shortening of the I-bands along the Z disc area in both iPSC-derived RAF1S257L cardiomyocytes and myocardial tissue biopsies. The aforementioned changes correlated with the isoform shift of titin from a longer (N2BA) to a shorter isoform (N2B) that also affected the active force generation and contractile tensions. The genotype-phenotype correlation was confirmed using cardiomyocyte progeny of an isogenic gene-corrected RAF1S257L-iPSC line and was mainly reversed by MEK inhibition. Collectively, our findings uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction that remarkably recapitulates the human disease. | |||||||
| Rechtliche Vermerke: | Originalveröffentlichung:
Nakhaeirad, S., Haghighi, F., Bazgir, F., Dahlmann, J., Busley, A. V., Buchholzer, M., Kleemann, K., Schänzer, A., Borchardt, A., Hahn, A., Kötter, S., Schanze, D., Anand, R., Funk, F., Kronenbitter, A., Scheller, J., Piekorz, R. P., Reichert, A., Volleth, M., … Ahmadian, M. R. (2023). Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues [OnlineRessource]. Communications Biology, 6, Article 657. https://doi.org/10.1038/s42003-023-05013-8 | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät Medizinische Fakultät | |||||||
| Dokument erstellt am: | 12.11.2024 | |||||||
| Dateien geändert am: | 12.11.2024 |
