AI Article Synopsis
- RASopathies, linked to gene mutations affecting the MAP kinase pathway, lead to various malformations, primarily causing cardiovascular disorders that increase mortality risk.
- The study evaluated cardiac tissue from children with RASopathy mutations using advanced techniques, revealing reduced cardiomyocyte volume and a significant increase in the number of these cells compared to controls and DCM patients.
- Findings suggest that juvenile RASopathy patients exhibit immature cardiomyocyte characteristics, with heart mass attributed to hyperplasia (more cells) rather than hypertrophy (larger cells), and the MAP kinase pathway was not activated in the cardiomyocytes of the studied patient.
Article Abstract
Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart.
Methods And Results: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4-10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected.
Conclusion: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy).
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| http://dx.doi.org/10.1016/j.yjmcc.2023.03.003 | DOI Listing |
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