Abstract
Arrhythmia is a major cause of sudden cardiac death and affects more than 14 million Americans. In familial cases, disease-causing mutations are expected to be found in genes encoding proteins that regulate membrane potential or calcium kinetics. Through genetic testing, we identified a ventricular fibrillation patient with family history of cardiovascular diseases that does not carry any disease-causing mutation in the arrhythmia-related genes. This patient, however, carries a previously reported dilated cardiomyopathy mutation (S130L) in presenilin-2 (PSEN2). To understand if this mutation can contribute to arrhythmia, the beating regularity and action potential morphology of cardiomyocytes derived from the patient-specific induced pluripotent stem cells (hiPSC-CMs) were assessed by fluorescence based membrane potential imaging. Up to 30% of these hiPSC-CMs demonstrated delayed after-depolarizations (DAD) and irregular beating pattern, which were prevented by correcting this PSEN2 mutation through CRISPR/Cas9 genome editing. Interestingly, we were unable to recapitulate the arrhythmic propensity by introducing this mutation into two healthy control hiPSC-CM lines, until we inserted another modulator mutation in histidine-rich calcium binding protein (HRC) that was also found in the patient, suggesting PSEN2 mutation is providing the substrate for arrhythmia induction. Mechanistically, compromised intracellular calcium removal was detected in S130L-PSEN2 hiPSC-CMs, which was concordant with a reduction in SERCA protein expression. Compromised calcium removal also led to elevated diastolic calcium and activated calcium/calmodulin-dependent protein kinase II (CAMKII), indicated by its enhanced phosphorylation. As a result, ryanodine receptor was hyper-phosphorylated at the CAMKII site (ser2814), which could facilitate calcium leakage from the ryanodine receptor and contribute to the occurrence of DAD. Collectively, our findings reveal a previously unknown function of PSEN2 in cardiomyocyte function and suggest that this PSEN2 mutation can compromise normal intracellular calcium cycling and contribute to arrhythmia through activating CAMKII.
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