Presentation Information
[II-TKIS-P-3]Cellular pathologies of severe cardiomyopathy in Noonan syndrome with multiple lentigines
○Sachie N. Nakagama1, Masamichi Ito2, Yu Nakagama1 (1.Gradate School of Medicine, Osaka Metropolitan University, Osaka, Japan, 2.The University of Tokyo Hospital, Tokyo, Japan)
Keywords:
Noonan syndrome with multiple lentigines,iPSC-derived cardiomyocyte,cardiomyopathy
[Background] RASopathy-associated cardiomyopathy (RAS-CMP) is thought to involve abnormalities in cardiomyocyte differentiation/maturation. In our previous work, we reported the presence of atypical cardiomyocytes in the extremely thickened hearts of patients with Noonan syndrome with multiple lentigines (NSML). In this study, we employed a cellular model to investigate the molecular determinants of severe phenotypic expression in NSML-associated cardiomyopathy (NSML-CMP).[Methods] A NSML-associated pathogenic PTPN11 G464A mutation was introduced to wild-type iPS cells by CRISPR-Cas9. Mutant and wild-type iPS cells were differentiated into cardiomyocytes (iPSCMs). Cellular phenotypes were analyzed, followed by profiling of underlying aberrancies in mitogenic signaling, using phospho-proteomics and RNA sequencing.[Results] NSML-CMP iPSCM exhibited abnormal cell-cell/cell-extracellular matrix adhesion, most evident under low-attachment or 3D culture conditions. The model recapitulated increased Ki-67 labeling (p<0.01) and enhanced receptor tyrosine kinase (RTK) signaling (p<0.001). mTORC inhibition partially reversed the phenotype, while additional pharmacological studies are ongoing to identify novel druggable targets.[Discussio Aberrant RTK signaling amplified by mitogenic networks drives cardiomyocyte abnormalities underlying myocardial thickening in NSML-CMP.