PLoS ONE (Jan 2018)

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 James,
  • J Peter van Tintelen,
  • Daniel P Judge,
  • Jan D H Jongbloed

DOI
https://doi.org/10.1371/journal.pone.0203078
Journal volume & issue
Vol. 13, no. 8
p. e0203078

Abstract

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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.