No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy

Edgar T Hoorntje, Anna Posafalvi, Petros Syrris, K Joeri van der Velde, Marieke C Bolling, Alexandros Protonotarios, Ludolf G Boven, Nuria Amat-Codina, Judith A Groeneweg, Arthur A Wilde, Nara Sobreira, Hugh Calkins, Richard N W Hauer, Marcel F Jonkman, William J McKenna, Perry M Elliott, Richard J Sinke, Maarten P van den Berg, Stephen P Chelko, Cynthia A JamesJ Peter van Tintelen, Daniel P Judge, Jan D H Jongbloed

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Abstract

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.

Original languageEnglish
Article numbere0203078
Number of pages14
JournalPLoS ONE
Volume13
Issue number8
DOIs
Publication statusPublished - 30-Aug-2018

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