Exploring the role of disease modifiers on the phenotypic variation of PLN R14del

Abstract

The PLN R14del mutation is an important genetic cause of both arrhythmogenic and dilated cardiomyopathies (ACM and DCM), and it is characterized by widely varying degrees of severity. The exact molecular mechanisms and reasons for its variable phenotype are not well understood yet. This review summarizes the current mechanistic insights into PLN R14del and explores multiple potential disease modifiers to better understand phenotypic variance. The loss of R14 alters the regulatory interaction between PLN and SERCA2a, disturbing calcium homeostasis and resulting in multiple downstream effects on proteostasis, metabolism, contractility, and tissue organization. These alterations ultimately predispose carriers to early arrhythmias and progressive systolic failure. Intrinsic differences between the left and right ventricles likely explain why disturbed calcium handling gives rise to both ACM- or DCM-like manifestations, although biventricular involvement is also common. Several modifiers may are thought to shift this balance or amplify disease severity. Aging, smoking, chronic kidney disease, and possibly high blood pressure have been associated with more severe disease, likely through declining cardiac reserves, impaired adrenergic stimulation, oxidative damage, inflammation, and hemodynamic load. These processes may further stress the already vulnerable PLN R14del myocardium and lower the threshold for maladaptive remodeling. Biological sex may also contribute to variability in severity as men often exhibit a more pronounced phenotype despite similar penetrance and mortality. The influence of several common modifiers, such as genetic background, lifestyle, environment, and comorbidities, has been limited or remains relatively unexplored. Other common cardiac risk factors, including physical or psychological stress, alcohol consumption, use of recreational drugs, and multiple cardiovascular and metabolic comorbidities, have not been linked to PLN R14del. Together, the available evidence supports a multi-hit model in which early defects in calcium handling initiate pathology, while ventricular biology and the influence of additional modifiers shape clinical expression. Understanding these interacting mechanisms provides a foundation for improving risk assessment and developing future targeted interventions and guidelines to slow or prevent PLN R14del disease progression.