264 Chapter 10 ABSTRACT The phospholamban (PLN) p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy (ACM), with the molecular disease mechanisms incompletely understood. Human-induced pluripotent stem cells (hiPSCs) clones were generated from three symptomatic and three non-symptomatic individuals carrying the Phospholamban (PLN) p.Arg14.del variant and two healthy probands from families carrying the mutation by reprogramming peripheral blood mononuclear cells (PBMCs) using integration-free Sendai viral vectors. The established hiPSCs clones had normal ES-like morphology, expression of pluripotency markers, karyotyping, and potential for mesoderm-cardiac lineage differentiation. The reported hiPSC lines would be a useful model for in vitro modeling of the PLN-R14del cardiomyopathy. 1. Resource utility The clinical spectrum of disease phenotype caused by PLN-R14del varies from healthy carriers to early stage ECG and ultrasound strain abnormalities to moderate stage consisting of decreased left ventricular function, and ultimately progression into congestive biventricular failure with/or arrhythmias. To unravel this variability in onset and disease penetrance, hiPSC clones were generated from the peripheral blood mononuclear cells (PBMCs) of symptomatic and non-symptomatic carriers from the PLNR14del mutation or from healthy family probands. The recent development of PLN-R14del mouse and zebrafish models, have helped identifying early-stage molecular mechanisms of PLN-R14del disease. Together with the clinical data and animals. However, animal models could give different outcomes than those found in clinical data and in vitro studies using hiPSC-derived cardiomyocytes. The generated hiPSC lines represent additional tools to compare symptomatic R14del carriers and the non-symptomatic carriers, for elucidating the molecular mechanism of the deletion of arginine 14 in dilated and arrhythmogenic cardiomyopathies.
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