Key result
CRISPR/Cas9 editing successfully generates PKP2 and DSG2 knock-out iPSCs to model arrhythmogenic cardiomyopathy in vitro.
Why the study?
Causal mutations in desmosomal proteins PKP2 and DSG2 underlie arrhythmogenic cardiomyopathy, but human isogenic in vitro models are needed to study disease mechanisms.
The generation of PKP2 and DSG2 knock-out iPSC lines provides a novel isogenic human in vitro model system for studying arrhythmogenic cardiomyopathy.
Enables mechanistic studies of arrhythmogenic cardiomyopathy in human iPSC models; leaves open clinical translation pending validation.
Arrhythmogenic cardiomyopathy (ACM) is characterized by fibro-fatty replacement of the myocardium, heart failure and life-threatening ventricular arrhythmias. Causal mutations were identified in genes encoding for proteins of the desmosomes, predominantly plakophilin-2 (PKP2) and desmoglein-2 (DSG2). We generated gene-edited knock-out iPSC lines for PKP2 (JMUi001-A-2) and DSG2 (JMUi001-A-3) using the CRISPR/Cas9 system in a healthy control iPSC background (JMUi001-A). Stem cell-like morphology, robust expression of pluripotency markers, embryoid body formation and normal karyotypes confirmed the generation of high quality iPSCs to provide a novel isogenic human in vitro model system mimicking ACM when differentiated into cardiomyocytes.
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Janz et al. (2021) studied Arrhythmogenic cardiomyopathy (ACM). CRISPR/Cas9-edited PKP2 knock-out and DSG2 knock-out iPSC lines vs. Healthy control iPSC background (JMUi001-A) was evaluated on Generation of high quality iPSCs (stem cell-like morphology, pluripotency markers, embryoid body formation, normal karyotypes). CRISPR/Cas9-edited PKP2 and DSG2 knock-out iPSC lines were successfully generated to provide an isogenic human in vitro model system for arrhythmogenic cardiomyopathy.
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