SYNPO2L Isoforms Regulate the Action Potential Characteristics and Contractility of Atrial Cardiomyocytes via YAP Signaling to Modulate Atrial Fibrillation Risk

Chandrakumar, R.; Shenwai, R. J.; Farshidfar, F.; Zhang, L.; Figarska, S.; Budan, A.; Cisne-Thompson, O.; Tefera, A. E.; Hoey, T.; Priest, J. R.; Tsui, J. H.

doi:10.1101/2025.08.03.668361

bioRxiv · 10.1101/2025.08.03.668361

SYNPO2L Isoforms Regulate the Action Potential Characteristics and Contractility of Atrial Cardiomyocytes via YAP Signaling to Modulate Atrial Fibrillation Risk

Chandrakumar, R.·Shenwai, R. J.·Farshidfar, F.·Zhang, L.·Figarska, S.·Budan, A.·Cisne-Thompson, O.·Tefera, A. E.·Hoey, T.·Priest, J. R.·Tsui, J. H.

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Abstract

BackgroundSYNPO2L is a component of the sarcomere Z-disk with two distinct isoforms (SYNPO2L_A and SYNPO2L_B) described to regulate actin bundle size. Common and rare variations in SYNPO2L have been implicated in risk for heart failure and atrial fibrillation (AF); however, little is known about the function or pathophysiological mechanism upon disease risk. MethodsThe role of SYNPO2L was explored with human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) models of a rare splicing mutation rs766868752 differentiated into both atrial and ventricular lineages. Electrophysiology was assessed via multi-electrode arrays (MEAs) and contractility was assessed using engineered heart tissues (EHTs). Genetic survival analyses were performed to explore the potential therapeutic role of the SYNPO2L_A isoform in AF risk after myocardial infarction. ResultshiPSC-CMs carrying the splice mutation rs766868752 resulted in preferential expression of the SYNPO2L_B isoform and absence of SYNPO2L_A isoform, and atrial hiPSC-CMs displayed significant differences in action potential durations when unpaced, and spontaneous extra-systolic beats when paced. Contractility of atrial hiPSC-CMs carrying the splice mutation was severely compromised. Electrophysiological differences were normalized and contractility was partially restored by overexpression with AAV:SYNPO2L_A. Absence of SYNPO2L_A in the mutant led to an observed decreased phosphorylation of YAP along with significant downstream transcriptional effects. A direct interaction between SYNPO2L_A and LATS2, a known regulator of YAP phosphorylation was found to occur in hiPSC-CMs. Additionally, a common variant time-to-event analysis may suggest a beneficial effect of the SYNPO2L_A isoform to lower the risk of atrial fibrillation after myocardial infarction. ConclusionsA rare splice mutation conferring isoform predominance of SYNPO2L_B appears to disturb the electrophysiology and contractility of atrial hiPSC-CMs via LATS2 phospho-regulatory effects upon YAP signaling. Supplementation of the SYNPO2L_A isoform can restore many functional deficits and supports a specific gene regulatory role for SYNPO2L in modulating the risk of AF and heart failure.

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Chandrakumar, R., Shenwai, R. J., Farshidfar, F., Zhang, L., Figarska, S., Budan, A., Cisne-Thompson, O., Tefera, A. E., Hoey, T., Priest, J. R., Tsui, J. H.. 2025-08-04. SYNPO2L Isoforms Regulate the Action Potential Characteristics and Contractility of Atrial Cardiomyocytes via YAP Signaling to Modulate Atrial Fibrillation Risk. https://doi.org/10.1101/2025.08.03.668361

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