Alteration of myocardial structure and function in RAF1associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs
Nakhaei-Rad, S.; Bazgir, F.; Dahlmann, J.; Busley, A. V.; Buchholzer, M.; Haghighi, F.; Schaenzer, A.; Hahn, A.; Koetter, S.; Schanze, D.; Anand, R.; Funk, F.; Borchardt, A.; Kronenbitter, A. V.; Scheller, J.; Piekorz, R. P.; Reichert, A.; Volleth, M.; Wolf, M. J.; Cirstea, I. C.; Gelb, B. D.; Tartaglia, M.; Schmitt, J.; Krueger, M.; Kutschka, I.; Cyganek, L.; Zenker, M.; Kensah, G.; Ahmadian, M. R.
Show abstract
Noonan syndrome (NS), the most common among the 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.770C>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 disease phenotype was partly reverted by using both MEK inhibition, and a gene-corrected isogenic RAF1L257S cell line. 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. These insights represent a basis to develop future targeted therapeutic approaches.
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