iPSC-derived cardiomyocytes from individuals with MYBPC3 intronic variants revealed mis-spliced mRNAs containing premature termination codons, with differential escape from nonsense-mediated decay.
Patient-derived iPSC-CMs successfully modeled the functional consequences of intronic MYBPC3 variants in hypertrophic cardiomyopathy, revealing differential mRNA degradation pathways.
Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and a leading cause of sudden death. Genetic testing and familial cascade screening play a pivotal role in the clinical management of HCM patients. However, conventional genetic tests primarily focus on the detection of exonic and canonical splice site variation. Oversighting intronic non-canonical splicing variants potentially contributes to a proportion of HCM patients remaining genetically undiagnosed. Here, using a non-integrative reprogramming strategy, we generated induced pluripotent stem cell (iPSC) lines from four individuals carrying one of two variants within intronic regions of MYBPC3: c.1224-52G > A and c.1898-23A > G. Upon differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), mis-spliced mRNAs were identified in cells harbouring these variants. Both abnormal mRNAs contained a premature termination codon (PTC), fitting the criteria for activation of nonsense mediated decay (NMD). However, the c.1898-23A > G transcripts escaped this mRNA quality control mechanism, while the c.1224-52G > A transcripts were degraded. The newly generated iPSC lines represent valuable tools for studying the functional consequences of intronic variation and for translational research aimed at reversing splicing abnormalities to prevent disease progression.
Jager et al. (Wed,) conducted a other in Hypertrophic Cardiomyopathy (n=4). Generation of induced pluripotent stem cell (iPSC) lines and differentiation to cardiomyocytes was evaluated on Identification of mis-spliced mRNAs and nonsense mediated decay activation. iPSC-derived cardiomyocytes from individuals with MYBPC3 intronic variants revealed mis-spliced mRNAs containing premature termination codons, with differential escape from nonsense-mediated decay.