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
2023 | journal article. A publication with affiliation to the University of Göttingen.
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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
Nakhaei-Rad, S.; Haghighi, F.; Bazgir, F.; Dahlmann, J.; Busley, A. V.; Buchholzer, M. & Kleemann, K. et al. (2023)
Communications Biology, 6(1). DOI: https://doi.org/10.1038/s42003-023-05013-8
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Details
- Authors
- Nakhaei-Rad, Saeideh; Haghighi, Fereshteh; Bazgir, Farhad; Dahlmann, Julia; Busley, Alexandra Viktoria; Buchholzer, Marcel; Kleemann, Karolin; Schänzer, Anne; Borchardt, Andrea; Hahn, Andreas; Ahmadian, Mohammad R.
- Abstract
- Abstract 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.
- Issue Date
- 2023
- Journal
- Communications Biology
- Project
- EXC 2067: Multiscale Bioimaging
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle - Working Group
- RG Cyganek (Stem Cell Unit)
- eISSN
- 2399-3642
- Language
- English
- Sponsor
- Bundesministerium für Bildung und Forschung https://doi.org/10.13039/501100002347
Deutsche Forschungsgemeinschaft https://doi.org/10.13039/501100001659
European Network on Noonan Syndrome and Related Disorders