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

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

Author information

1
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
2
Durrer Cardiovascular Research Center/Netherlands Heart Institute, Utrecht, the Netherlands.
3
Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom.
4
Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
5
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America.
6
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
7
Heart Centre, Department of Clinical and Experimental Cardiology, Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
8
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia.
9
Department of Genetics, Johns Hopkins University School of Medicine, Baltimore, United States of America.
10
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
11
Department of Clinical Genetics, Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
12
Medical University of South Carolina, Charleston, United States of America.

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.

PMID:
30161220
PMCID:
PMC6117038
DOI:
10.1371/journal.pone.0203078
[Indexed for MEDLINE]
Free PMC Article

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