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The article presents an editorial which discusses several aspects associated with the nonsense-mediated mRNA decay (NMD) in hypertrophic cardiomyopathy. The topics addressed include details on the chronic activation of NMD is the underlying mechanism by which truncating mutations in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C) cause molecular abnormalities associated with hypertrophic cardiomyopathy (HCM).

Introduction: Cardiomyopathy (CMP) is a heterogeneous disease group affecting heart function and may lead to heart failure. Genetic variants in more than 50 genes have been linked to CMP phenotypes. The understanding of the natural course and the underlying molecular mechanisms of pediatric CMP and heart failure is incomplete. Hypothesis: This study aims to establish the abundance of genetic variants in known CMP disease genes in a large cohort of pediatric CMP patients. Methods: To identify genetic defects in pediatric CMP we investigated a cohort of patients

Cardiac hypertrophy is the heart's main adaption to hemodynamic stress and can proceed to heart failure as a frequent cause of death. A growing number of molecular mediators has been elucidated, including the phosphatase Calcineurin and its target, the NFAT transcription factors. Additionally, epigenetic transcriptional regulation, such as DNA-methylation is another major, highly conserved layer of regulation in establishing and perpetuating transcription in cardiac hypertrophy and heart failure. We combined whole genome bisulfite sequencing and RNA-sequencing in adult murine cardiac myocytes isolated from Calcineurin-transgenic mice as a model of hypertrophy. We integrated our data on genome-wide DNA methylation and transcription with datasets of cardiac enhancer regions to correlate methylation at enhancers, promoters and gene bodies with transcriptional activity at corresponding sites. Using functional annotation of differentially expressed transcripts and methylated regions, we categorized enriched and potentially novel pathways with a role in cardiac hypertrophy. We identified 7102 differentially methylated regions (DMRs). RNA-sequencing revealed 3395 transcripts which were significantly differentially regulated, 200 of which show a more than twofold higher level of induction or repression, including genes that are known to play a role in cardiac hypertrophy and disease, such as Nppa , Nppb or Myh7. From this list, we validated differential expression of Ror2 , Leprel1 , Vash2 , Apol6 and Barx2 in several different models of cardiac hypertrophy (mechanic stretch, phenylephrine, TAC-surgery) and patient samples of cardiomyopathies. Taken together, we performed an unbiased, genome-wide analysis of the landscape of DNA-methylation and transcription in Calcineurin-transgenic mice. A further characterization of our novel targets seems promising to gain new insights in molecular mechanisms of cardiac muscle disease and may lay on the ground to develop new diagnostic or therapeutic options. [ABSTRACT FROM AUTHOR]