Title : ( Alteration of myocardial structure and function in RAF1-associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs )
Authors: Saeideh Nakhaeirad , Farhad Bazgir , Julia Dahlmann , Alexandra Viktoria Busley , Marcel Buchholzer , Fereshteh Haghighi , Anne Schanzer , Andreas Hahn , Sebastian Kotter , Denny Schanze , Ruchika Anand , Florian Funk , Andrea Borchardt , Annette Vera Kronenbitter , Jurgen Scheller , Roland P. Piekorz , Andreas S. Reichert , Marianne Volleth , Matthew J. Wolf , Ion Cristian Cirstea , Bruce D. Gelb , Marco Tartaglia , Joachim Schmitt , Martina Kruger , ngo Kutschka , Lukas Cyganek , Martin Zenker , George Kensah , Mohammad R. Ahmadian ,Access to full-text not allowed by authors
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.