Journal article

Authors list: Nakhaei-Rad, Saeideh; Haghighi, Fereshteh; Bazgir, Farhad; Dahlmann, Julia; Busley, Alexandra Viktoria; Buchholzer, Marcel; Kleemann, Karolin; Schaenzer, Anne; Borchardt, Andrea; Hahn, Andreas; Koetter, Sebastian; Schanze, Denny; Anand, Ruchika; Funk, Florian; Kronenbitter, Annette Vera; Scheller, Juergen; Piekorz, Roland P.; Reichert, Andreas S.; Volleth, Marianne; Wolf, Matthew J.; Cirstea, Ion Cristian; Gelb, Bruce D.; Tartaglia, Marco; Schmitt, Joachim P.; Krueger, Martina; Kutschka, Ingo; Cyganek, Lukas; Zenker, Martin; Kensah, George; Ahmadian, Mohammad R.

Publication year: 2023

Journal: Communications Biology

Volume number: 6

Issue number: 1

eISSN: 2399-3642

Open access status: Gold

DOI Link: https://doi.org/10.1038/s42003-023-05013-8

Publisher: Nature Research

Abstract: 

Studies on 3D bioartificial cardiac tissues reveal the impacts of hypertrophic cardiomyopathy-associated RAF1 mutations on sarcomere structure, contractile behavior, Ca2+ handling, and intracellular signaling.

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 RAF1(S257L) 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 RAF1(S257L) 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 RAF1(S257L)-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.

Harvard Citation style: Nakhaei-Rad, S., Haghighi, F., Bazgir, F., Dahlmann, J., Busley, A., Buchholzer, M., et al. (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, Communications Biology, 6(1), Article 657. https://doi.org/10.1038/s42003-023-05013-8

APA Citation style: Nakhaei-Rad, S., Haghighi, F., Bazgir, F., Dahlmann, J., Busley, A., Buchholzer, M., Kleemann, K., Schaenzer, A., Borchardt, A., Hahn, A., Koetter, S., Schanze, D., Anand, R., Funk, F., Kronenbitter, A., Scheller, J., Piekorz, R., Reichert, A., Volleth, M., ...Ahmadian, M. (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. Communications Biology. 6(1), Article 657. https://doi.org/10.1038/s42003-023-05013-8