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

Meier AB, Murthi SR, Rawat H, Toepfer CN, Santamaria G, Schmid M, Mastantuono E, Schwarzmayr T, Berutti R, Cleuziou J, Ewert P, Gorlach A, Klingel K, Laugwitz KL, Seidman CE, Seidman JG, Moretti A, Wolf CM (2022)


Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 25

Article Number: 103596

Journal Issue: 1

DOI: 10.1016/j.isci.2021.103596

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.

Involved external institutions

How to cite

APA:

Meier, A.B., Murthi, S.R., Rawat, H., Toepfer, C.N., Santamaria, G., Schmid, M.,... Wolf, C.M. (2022). Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome. iScience, 25(1). https://doi.org/10.1016/j.isci.2021.103596

MLA:

Meier, Anna B., et al. "Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome." iScience 25.1 (2022).

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