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

Nienke M. Stege, Rudolf A. de Boer, Catherine A. Makarewich, Peter van der Meer, Herman H.W. Silljé^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

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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.

Original language	English
Pages (from-to)	1041-1052
Number of pages	12
Journal	JACC: Basic to Translational Science
Volume	9
Issue number	8
DOIs	https://doi.org/10.1016/j.jacbts.2024.02.017
Publication status	Published - Aug-2024

Keywords

aggregation
cardiomyopathy
disease mechanism
p.Arg14del
phospholamban
sarcoplasmic reticulum
SERCA

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@article{183c86797f1242acb93559c8ba8afbb2,

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

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 = "aggregation, cardiomyopathy, disease mechanism, p.Arg14del, phospholamban, sarcoplasmic reticulum, SERCA",

author = "Stege, {Nienke M.} and {de Boer}, {Rudolf A.} and Makarewich, {Catherine A.} and {van der Meer}, Peter and Sillj{\'e}, {Herman H.W.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = aug,

doi = "10.1016/j.jacbts.2024.02.017",

language = "English",

volume = "9",

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T1 - Reassessing the Mechanisms of PLN-R14del Cardiomyopathy

T2 - From Calcium Dysregulation to S/ER Malformation

AU - Stege, Nienke M.

AU - de Boer, Rudolf A.

AU - Makarewich, Catherine A.

AU - van der Meer, Peter

AU - Silljé, Herman H.W.

PY - 2024/8

Y1 - 2024/8

N2 - 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.

AB - 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.

KW - aggregation

KW - cardiomyopathy

KW - disease mechanism

KW - p.Arg14del

KW - phospholamban

KW - sarcoplasmic reticulum

KW - SERCA

UR - http://www.scopus.com/inward/record.url?scp=85191796471&partnerID=8YFLogxK

U2 - 10.1016/j.jacbts.2024.02.017

DO - 10.1016/j.jacbts.2024.02.017

M3 - Review article

AN - SCOPUS:85191796471

SN - 2452-302X

VL - 9

SP - 1041

EP - 1052

JO - JACC: Basic to Translational Science

JF - JACC: Basic to Translational Science

IS - 8

ER -

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

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