Figure 7.

Proposed disease mechanisms as a result of age-related alternative splicing. All carriers in this model are heterozygous for one of the variants and produce wt protein from at least one allele at all times. Young and middle-aged MYBPC3^Δ25bp carriers predominantly produce wt mRNA from both alleles, resulting in mild or absent symptoms. Incorporation of MyBPC^D389V into the contractile zone of sarcomeres in young and middle-aged MYBPC3^Δ25bp/D389V carriers leads to myocardial remodeling mediated by a poison polypeptide mechanism. As patients age, the alternatively spliced transcript on the allele carrying the intron deletion predominates in both MYBPC3^Δ25bp and MYBPC3^Δ25bp/D389V carriers. We assume that the truncated forms of the protein are efficiently eliminated by the ubiquitin–proteasome system in cardiomyocytes with smaller fractions of MyBPC^C10mut and MyBPC^D389V/C10mut mislocalizing to the Z-disc. As a result, C-zone haploinsufficiency is predicted to become the dominant disease mechanism in elderly MYBPC3^Δ25bp and MYBPC3^Δ25bp/D389V carriers.