Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation

Nienke M Stege; Rudolf A de Boer; Catherine A Makarewich; Peter van der Meer; Herman H W Silljé

doi:10.1016/j.jacbts.2024.02.017

Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation

JACC Basic Transl Sci. 2024 Apr 17;9(8):1041-1052. doi: 10.1016/j.jacbts.2024.02.017. eCollection 2024 Aug.

Authors

Nienke M Stege¹, Rudolf A de Boer², Catherine A Makarewich^{3

4}, Peter van der Meer¹, Herman H W Silljé¹

Affiliations

¹ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
² Erasmus Medical Center, Cardiovascular Institute, Thorax Center, Department of Cardiology, Rotterdam, the Netherlands.
³ Division of Molecular Cardiovascular Biology of the Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
⁴ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Abstract

The phospholamban (PLN) pathogenic gene variant, p.Arg14del (PLN-R14del), can lead to dilated and arrhythmogenic cardiomyopathy, resulting in heart failure. PLN-R14del cardiomyopathy has been conceptualized as a disease caused by sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) superinhibition. However, recent studies raised controversy regarding the effect of PLN-R14del on SERCA activity and revealed a prominent role for abnormal PLN protein distribution and sarco/endoplasmic reticulum disorganization as underlying disease mechanism. Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove more effective than SERCA activity modulation. This review reassesses the disease mechanisms of PLN-R14del cardiomyopathy and emphasizes the importance of dissecting the underlying molecular mechanisms to uncover targets for innovative treatments.

Keywords: SERCA; aggregation; cardiomyopathy; disease mechanism; p.Arg14del; phospholamban; sarcoplasmic reticulum.

Publication types

Review