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

doi:10.1016/j.isci.2021.103596

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

iScience. 2021 Dec 9;25(1):103596. doi: 10.1016/j.isci.2021.103596. eCollection 2022 Jan 21.

Authors

Anna B Meier^{1

2}, Sarala Raj Murthi³, Hilansi Rawat^{1

2}, Christopher N Toepfer^{4

5

6}, Gianluca Santamaria^{1

2}, Manuel Schmid⁵, Elisa Mastantuono^{7

2}, Thomas Schwarzmayr^{7

2}, Riccardo Berutti^{8

9}, Julie Cleuziou^{10

11}, Peter Ewert^{3

2}, Agnes Görlach^{3

2}, Karin Klingel¹², Karl-Ludwig Laugwitz^{1

2}, Christine E Seidman⁴, Jonathan G Seidman⁴, Alessandra Moretti^{1

2}, Cordula M Wolf^{3

2}

Affiliations

¹ First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany.
² DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany.
³ Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich 80636, Germany.
⁴ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁵ Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
⁶ Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁷ Institute of Human Genetics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
⁸ Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany.
⁹ Institute of Neurogenomics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
¹⁰ Department of Congenital and Pediatric Heart Surgery, German Heart Center Munich, Technical University of Munich, Munich 80636, Germany.
¹¹ INSURE (Institute for Translational Cardiac Surgery), Department of Cardiovascular Surgery, German Heart Center Munich, Technical University of Munich, Munich 80636, Germany.
¹² Institute for Pathology and Neuropathology, Department of Cardiopathology, University Hospital Tuebingen, Tuebingen 72076, Germany.

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 PTPN11 ^N308S/+ 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.

Keywords: Cell biology; Stem cells research; Transcriptomics.

Abstract

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