Studies on a mouse model of Arrhythmogenic Cardiomyopathy (ACM) reveal a central role for Alternative Splicing (AS) in arrythmogenesis.



ACM is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Global gene and protein expression studies performed so far had not revealed the molecular mechanisms of PLN-R14del ACM pathogenesis. Using a humanized PLN-R14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), researchers led by P. Kafasla at IFBR, BSRC “Alexander Fleming” and D. Sanoudou at the Medical School of the National and Kapodistrian University of Athens investigated the transcriptome-wide AS changes associated with the R14del mutation. These analyses revealed distinct AS profiles in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Deregulated AS of key genes encoding proteins that regulate calcium homeostasis in the heart were significantly altered in PLN-R14del mouse hearts and human iPSC-CM thus, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM. Thus, this new collaborative study reveals the regulatory role of AS in the molecular mechanisms of PLN-R14del ACM pathogenesis.

Rogalska ME, Vafiadaki E, Erpapazoglou Z, Haghighi K, Green L, Mantzoros CS, Hajjar RJ, Tranter M, Karakikes I, Kranias EG, Stillitano F, Kafasla P*, Sanoudou D*.
Isoform changes of action potential regulators in the ventricles of arrhythmogenic phospholamban-R14del humanized mouse hearts. Metabolism. 2022 Nov 11:155344. *: equal contribution.
doi: 10.1016/j.metabol.2022.155344.