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
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Published:2023-06-21
Issue:1
Volume:6
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Nakhaei-Rad Saeideh, Haghighi Fereshteh, Bazgir FarhadORCID, Dahlmann Julia, Busley Alexandra Viktoria, Buchholzer MarcelORCID, Kleemann Karolin, Schänzer Anne, Borchardt Andrea, Hahn Andreas, Kötter Sebastian, Schanze DennyORCID, Anand Ruchika, Funk Florian, Kronenbitter Annette Vera, Scheller Jürgen, Piekorz Roland P., Reichert Andreas S., Volleth MarianneORCID, Wolf Matthew J., Cirstea Ion CristianORCID, Gelb Bruce D.ORCID, Tartaglia Marco, Schmitt Joachim P., Krüger Martina, Kutschka Ingo, Cyganek Lukas, Zenker MartinORCID, Kensah GeorgeORCID, Ahmadian Mohammad R.ORCID
Abstract
AbstractNoonan 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.
Funder
Bundesministerium für Bildung und Forschung Deutsche Forschungsgemeinschaft European Network on Noonan Syndrome and Related Disorders
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference92 articles.
1. Pandit, B. et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat. Genet. 39, 1007–1012 (2007). 2. Razzaque, M. A. et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 39, 1013–1017 (2007). 3. Maron, B. J. & Maron, M. S. Hypertrophic cardiomyopathy. Lancet 381, 242–255 (2013). 4. Rezaei Adariani, S. et al. Structural snapshots of RAF kinase interactions. Biochem. Soc. Trans. 46, 1393–1406 (2018). 5. Desideri, E., Cavallo, A. L. & Baccarini, M. Alike but different: RAF paralogs and their signaling outputs. Cell 161, 967–970 (2015).
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