Central Illustration.

PLN-R14del Disease Mechanism and Therapies

The Central Illustration presents both original and novel insights into PLN-R14del disease mechanisms and potential therapeutic targets. Panel 1 illustrates the genetic mutation and proposes potential treatment approaches such as gene therapy or gene silencing of PLN mRNA. In panel 2a, the conventional view of the PLN-R14del disease mechanism is depicted, while in panel 2b, our novel insights and potential targeting of abnormal S/ER clusters by DWORF are highlighted. Panel 3 portrays the resulting cell death and replacement fibrosis contributing to ACM and DCM, with potential symptom management through interventions like ICD or standard HF medication, although these do not address the underlying disease itself. Ca²⁺ = calcium; HF = heart failure; ICD = implantable cardioverter-defibrillator; PLN = phospholamban; SERCA2a = sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a; S/ER = sarco/endoplasmic reticulum.