Unraveling the Pathophysiological Mechanisms of Phospholamban R14del Cardiomyopathy: A Comprehensive Overview

Sep 24, 2025Circulation. Heart failure

Understanding How the Phospholamban R14del Mutation Affects Heart Muscle Disease

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Abstract

The PLN-R14del mutation has been identified in numerous patients across 11 countries.

PLN-R14del carriers frequently display both dilated cardiomyopathy and arrhythmogenic cardiomyopathy.
This mutation is linked to a significant portion of annual heart transplants in the Netherlands.
PLN plays an essential role in regulating the calcium pump in heart cells.
The exact mechanisms of how PLN-R14del leads to heart disease are still unclear.
Existing literature on the PLN-R14del mutation is reviewed to clarify its pathological effects.

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The discovery of the PLN-R14del (deletion of arginine 14 [p.Arg14del] within the phospholamban protein) genetic mutation, characterized by a deletion of R14 in phospholamban, in a large Greek family marked a significant milestone in understanding the cause of its associated cardiomyopathy. Since its initial identification in 2006, this mutation has been found in numerous patients across 11 countries. PLN-R14del carriers commonly exhibit both dilated cardiomyopathy and arrhythmogenic cardiomyopathy, accounting for a significant portion of annual heart transplants in the Netherlands. Under physiological conditions, PLN plays a crucial role in regulating the calcium pump SERCA2a (sarco[endo]plasmic reticulum calcium ATPase 2a) within cardiomyocytes. While the normal function of PLN has been extensively studied, the precise mechanisms underlying the pathogenesis of PLN-R14del-induced heart disease remain uncertain and subject to ongoing debate. The current review systematically summarizes existing literature on the PLN-R14del mutation, elucidating its pathological phenotypes and discussing its implications in PLN-R14del cardiomyopathy. Current knowledge is consolidated, and unresolved questions are addressed with the aim to contribute to a deeper understanding of PLN-R14del-associated cardiac pathology. Finally, this review provides guidance for future research to advance diagnosis and therapeutic approaches for affected individuals.

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Unraveling the Pathophysiological Mechanisms of Phospholamban R14del Cardiomyopathy: A Comprehensive Overview

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