TY - JOUR
T1 - Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy
AU - te Rijdt, Wouter P.
AU - Asimaki, Angeliki
AU - Jongbloed, Jan D.H.
AU - Hoorntje, Edgar T.
AU - Lazzarini, Elisabetta
AU - van der Zwaag, Paul A.
AU - de Boer, Rudolf A.
AU - van Tintelen, J. Peter
AU - Saffitz, Jeffrey E.
AU - van den Berg, Maarten P.
AU - Suurmeijer, Albert J.H.
N1 - Funding Information:
Funding: This work was financially supported by a grant from the Fondation Leducq (CurePLaN) and the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (The Hague, the Netherlands): CVON2012–10 PREDICT, CVON2014–40 DOSIS and CVON 2015–12 eDETECT projects. Wouter P. te Rijdt is supported by Young Talent Program (CVON PREDICT) grant 2017 T001 from the Dutch Heart Foundation. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Publisher Copyright:
© 2018 Elsevier Inc.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity.
AB - Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity.
KW - Arrhythmogenic cardiomyopathy
KW - Dilated cardiomyopathy
KW - Immunofluorescence
KW - Next-generation sequencing
KW - Phospholamban
KW - Sequence Deletion
KW - Prognosis
KW - Humans
KW - Middle Aged
KW - Male
KW - Myocardium/chemistry
KW - Tight Junction Proteins/analysis
KW - Adipose Tissue/pathology
KW - Adult
KW - Female
KW - Registries
KW - Arrhythmogenic Right Ventricular Dysplasia/genetics
KW - Cardiomyopathy, Dilated/genetics
KW - Genetic Predisposition to Disease
KW - Risk Factors
KW - Desmosomes/chemistry
KW - Genetic Markers
KW - Phenotype
KW - Calcium-Binding Proteins/genetics
KW - Fibrosis
KW - Aged
UR - https://www.scopus.com/pages/publications/85061227954
U2 - 10.1016/j.carpath.2018.12.006
DO - 10.1016/j.carpath.2018.12.006
M3 - Article
C2 - 30763825
SN - 1054-8807
VL - 40
SP - 2
EP - 6
JO - Cardiovascular Pathology
JF - Cardiovascular Pathology
ER -