Journal
ISCIENCE
Volume 25, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.103596
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Funding
- European Research Council [ERC 788381]
- German Research Foundation, Transregio Research Unit 152
- DZHK (German Centre for Cardiovascular Research)
- Deutsche Herzstiftung e.V. Gerd-Killian Award
- Sir Henry Wellcome Fellowship [206466/Z/17/Z]
- German Research Foundation, Transregio Research Unit 267
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The cardiomyopathy associated with Noonan syndrome (NS-CM) and hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM) exhibit distinct disease phenotypes and potential different pathophysiology.
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.
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