LAUSR

The adult heart is 1 of the tissues least capable of regeneration and repair, with estimates of ≈0.5% to 2% nuclear DNA synthesis events per year in cardiomyocytes.1 Hence, it requires efficient surveillance systems to maintain cardiomyocyte homeostasis for proper cardiac function. Proteostasis is preserved by the protein quality control system that refolds misfolded or mutant proteins by molecular chaperones or degrades them by 1 of the 2 major proteolytic systems, which are the ubiquitin-proteasome system2 and autophagy.3 Beside the protein quality control system, the term mRNA surveillance was coined 25 years ago to describe the mechanism by which nonsense codons are recognized and nonsense mRNAs are eliminated.4 The nonsense-mediated mRNA decay (NMD) has traditionally been described as an eukaryotic mRNA surveillance pathway for nonsense mRNAs harboring a premature termination codon.5 The central player of NMD is the ATP-dependent RNA helicase UPF1 (up-frameshift 1) that recognizes the mRNA target and recruits several other NMD factors to bridge the exon junction complex and initiate degradation of the mRNA target. UPF1 phosphorylation and subsequent dephosphorylation are required to activate NMD. Another mechanism of NMD activation depends on the distance between the premature termination codon and the poly(A).5 Despite 3 decades of research and the discovery of several factors and enzymes involved, the exact mechanisms and criteria for selective mRNA degradation are still not fully understood. In the present issue of Circulation, Seeger et al6 report that chronic activation of NMD is the underlying mechanism by which truncating mutations in MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), cause molecular abnormalities associated with hypertrophic cardiomyopathy (HCM). HCM is 1 of the most common cardiac genetic diseases, affecting ≈1:500 individuals and transmitted as an autosomal-dominant trait. It is recognized as a sarcomeric disease with MYBPC3 being the most frequently mutated gene, accounting for ≈50% of the molecularly identified cases.7 At least two-thirds of MYBPC3 mutations are truncating, resulting in nonsense mRNAs harboring a premature termination codon.8 Nonsense MYBPC3 mRNA and truncated cMyBP-C were barely detected, if at all, in several HCM septal myectomies,9–11 and findings in mice suggested that NMD and the ubiquitin-proteasome system act as parallel quality control systems to eliminate nonsense mRNA and mutant cMyBP-C to prevent potential accumulation of toxic aggregates.12 Most of the studies showed a reduced amount of full-length cMyBP-C protein in human and mouse cardiac tissues, suggesting cMyBP-C haploinsufficiency as a prevailing HCM disease mechanism (for review, see reference 7). However, a recent study challenged this concept, because the level of cMyBP-C did not differ between samples of patients with HCM carrying © 2019 American Heart Association, Inc.