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Nakhaei-Rad, Saeideh; Haghighi, Fereshteh; Bazgir, Farhad; Dahlmann, Julia; Busley, Alexandra Viktoria; Buchholzer, Marcel; Kleemann, Karolin; Schänzer, Anne; Borchardt, Andrea; Hahn, Andreas; Kötter, Sebastian; Schanze, Denny; Anand, Ruchika; Funk, Florian; Kronenbitter, Annette Vera; Scheller, Jürgen; Piekorz, Roland P.; Reichert, Andreas S.; Volleth, Marianne; Wolf, Matthew J.; Cirstea, Ion Cristian; Gelb, Bruce D.; Tartaglia, Marco; Schmitt, Joachim P.; [...]

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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  • Medientyp: E-Artikel
  • Titel: 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
  • Beteiligte: Nakhaei-Rad, Saeideh; Haghighi, Fereshteh; Bazgir, Farhad; Dahlmann, Julia; Busley, Alexandra Viktoria; Buchholzer, Marcel; Kleemann, Karolin; Schänzer, Anne; Borchardt, Andrea; Hahn, Andreas; Kötter, Sebastian; Schanze, Denny; Anand, Ruchika; Funk, Florian; Kronenbitter, Annette Vera; Scheller, Jürgen; Piekorz, Roland P.; Reichert, Andreas S.; Volleth, Marianne; Wolf, Matthew J.; Cirstea, Ion Cristian; Gelb, Bruce D.; Tartaglia, Marco; Schmitt, Joachim P.; [...]
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Communications Biology
  • Sprache: Englisch
  • DOI: 10.1038/s42003-023-05013-8
  • ISSN: 2399-3642
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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<jats:sup>S257L</jats:sup> and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic <jats:italic>RAF1</jats:italic> c.770 C &gt; 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<jats:sup>S257L</jats:sup> 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<jats:sup>S257L</jats:sup>-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.</jats:p>
  • Zugangsstatus: Freier Zugang