TY - JOUR
T1 - No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy
AU - Hoorntje, Edgar T.
AU - Posafalvi, Anna
AU - Syrris, Petros
AU - Van Der Velde, K. Joeri
AU - Bolling, Marieke C.
AU - Protonotarios, Alexandros
AU - Boven, Ludolf G.
AU - Amat-Codina, Nuria
AU - Groeneweg, Judith A.
AU - Wilde, Arthur A.
AU - Sobreira, Nara
AU - Calkins, Hugh
AU - Hauer, Richard N.W.
AU - Jonkman, Marcel F.
AU - McKenna, William J.
AU - Elliott, Perry M.
AU - Sinke, Richard J.
AU - Van Den Berg, Maarten P.
AU - Chelko, Stephen P.
AU - James, Cynthia A.
AU - Van Tintelen, J. Peter
AU - Judge, Daniel P.
AU - Jongbloed, Jan D.H.
N1 - Funding Information:
The work was financially supported by the Netherlands Cardiovascular Research Initiative of the Dutch Heart Foundation (CVON2012-10 PREDICT and CVON 2014-40 DOSIS projects), the Baylor-Hopkins Center for Mendelian Genomics, which is funded by a grant from the NHGRI/NHLBI (2UM1HG006542), the Netherlands Organisation for Scientific Research (NWO, visitor’s travel grant 040.11.586 to C.A. James and NWO VIDI grant number 917.164.455 for K.J. van der Velde) and the Johns Hopkins ARVD Program. University College London/University College London Hospitals NHS Foundation Trust receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre funding scheme. UCL Centre for Heart Muscle Disease was funded by a Foundation Leducq Transatlantic Networks of Excellence Program: grant no 14 CVD 03. The Johns Hopkins ARVD/C Program is supported by the Dr. Francis P. Chiaramonte Private Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments. This publication was made possible by the Johns Hopkins Institute for Clinical and Translational Research (ICTR) which is funded in part by Grant Number UL1 TR001079 from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS or NIH.
Publisher Copyright:
© 2018 Hoorntje et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/8
Y1 - 2018/8
N2 - Aims Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. Methods We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. Results Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. Conclusions Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.
AB - Aims Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. Methods We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. Results Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. Conclusions Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.
UR - http://www.scopus.com/inward/record.url?scp=85052835943&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052835943&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0203078
DO - 10.1371/journal.pone.0203078
M3 - Article
C2 - 30161220
AN - SCOPUS:85052835943
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 8
M1 - e0203078
ER -