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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.
- Source :
-
Communications biology [Commun Biol] 2023 Jun 21; Vol. 6 (1), pp. 657. Date of Electronic Publication: 2023 Jun 21. - Publication Year :
- 2023
-
Abstract
- 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 <superscript>S257L</superscript> 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 RAF1 <superscript>S257L</superscript> 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 <superscript>S257L</superscript> -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.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Germ-Line Mutation
Myocytes, Cardiac metabolism
Signal Transduction
Cardiomyopathy, Hypertrophic genetics
Cardiomyopathy, Hypertrophic metabolism
Cardiomyopathy, Hypertrophic pathology
Noonan Syndrome genetics
Noonan Syndrome complications
Noonan Syndrome metabolism
Proto-Oncogene Proteins c-raf genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2399-3642
- Volume :
- 6
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Communications biology
- Publication Type :
- Academic Journal
- Accession number :
- 37344639
- Full Text :
- https://doi.org/10.1038/s42003-023-05013-8