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

Abstract

Summary 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.

LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome

“…Interestingly, no myofibrillar disarray was observed in our cell model. However, the presence of myofibril disarray in NS remains controversial: whereas structural defects were described in RAF1-associated iPSC models, 15,39 we and others did not observe any impact on sarcomere structures or myofibril organization in LZTR1-related, PTPN11-related, and BRAF-related iPSC-CMs, 10,14,16 implying potential genotype-dependent differences in the manifestation of myofibril disassembly in NS.…”

Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease

“…6i). We recently reported that hiPSC-derived CMs from this individual displayed cell cycle defects, leading to hyperproliferation rather than a classical hypertrophic phenotype when cultured in 2D 60 . The same was observed in individual-specific epicardioids; they did not have larger CMs than healthy controls and did not upregulate hypertrophy markers but showed increased CM proliferation across the myocardial layers (Supplementary Fig.…”

Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2

“…When differentiated into cardiomyocytes these cells show a phenotype consistent with cardiac hypertrophy, with larger surface area compared to wt-iPSCs and HES2 cells, increased sarcomere assembly and nuclear localization of NFATc4. In contrast, both cardiac tissue from NS patients with CRAF and SHP2 variants, and iPSCs with SHP2-N308S variant, display cellular hyperplasia, rather than hypertrophy, which is presumably due to the increased cell cycle progression (Meier et al, 2021). However, hypertrophic phenotypes are observed in cardiomyocytes differentiated from NS-derived iPSCs with CRAF mutations (Jaffré et al, 2019;Nakhaei-Rad et al, 2022).…”

“…As human model for NS and NSML, patient derived iPSCs containing SHP2 variants, are used to study cardiac, neuronal and hematopoietic defects (Carvajal-Vergara et al, 2010;Hamada et al, 2020;Li et al, 2019;Meier et al, 2021;Mulero-Navarro et al, 2015;Pearson et al, 2020). The first iPSCs with SHP2 variants were derived more than a decade ago from skin fibroblasts of two NSML patients carrying the SHP2-T468M mutation (Carvajal-Vergara et al, 2010).…”