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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\n                    <jats:sup>S257L<\/jats:sup>\n                    and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic\n                    <jats:italic>RAF1<\/jats:italic>\n                    c.770\u2009C\u2009&gt;\u2009T missense change. We characterize the molecular, structural, and functional consequences of aberrant RAF1\u2013associated 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\n                    <jats:sup>S257L<\/jats:sup>\n                    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\n                    <jats:sup>S257L<\/jats:sup>\n                    -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.\n                  <\/jats:p>","DOI":"10.1038\/s42003-023-05013-8","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T07:02:15Z","timestamp":1687330935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["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 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B.D.G.\u00a0is a consultant for Day One Biopharmaceuticals and was recently a consultant for BioMarin. He received a sponsored research award from Onconova. M.Z. is a member of a scientific advisory board for Day One Biopharmaceuticals.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Blood samples and dermal fibroblasts were obtained by skin biopsy from two unrelated female patients with Noonan syndrome carrying the heterozygous substitution c.770\u2009C>T in exon 7 of RAF1 under protocols concerning research with biomaterials approved by the institution\u2019s ethics committees (Justus-Liebig-University Giessen, Germany: AZ258\/16; Otto von Guericke University Medical Center Magdeburg: 173\/14; University Medical Center G\u00f6ttingen: 10\/9\/15). Research with biomaterials was approved by the ethical committee of the Justus Liebig University of Giessen. Written informed consent was given by both parents of both individuals. 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