Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome

Anna B. Meier, Sarala Raj Murthi, Hilansi Rawat, Christopher N. Toepfer, Gianluca Santamaria, Manuel Schmid, Elisa Mastantuono, Thomas Schwarzmayr, Riccardo Berutti, Julie Cleuziou, Peter Ewert, Agnes Görlach, Karin Klingel, Karl Ludwig Laugwitz, Christine E. Seidman, Jonathan G. Seidman, Alessandra Moretti, Cordula M. Wolf

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.

Original languageEnglish
Article number103596
JournaliScience
Volume25
Issue number1
DOIs
StatePublished - 21 Jan 2022

Keywords

  • Cell biology
  • Stem cells research
  • Transcriptomics

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