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

PLoS One. 2018 Aug 30;13(8):e0203078. doi: 10.1371/journal.pone.0203078. eCollection 2018.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Arrhythmogenic Right Ventricular Dysplasia / metabolism*
  • Arrhythmogenic Right Ventricular Dysplasia / pathology
  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Gene Frequency
  • Genetic Variation
  • Heterozygote
  • Humans
  • Myocardium / metabolism
  • Myocardium / pathology
  • Plectin / genetics*
  • Plectin / metabolism*

Substances

  • PLEC protein, human
  • Plectin