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- Title
No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy.
- Authors
Hoorntje, Edgar T.; Posafalvi, Anna; Syrris, Petros; van der Velde, K. Joeri; Bolling, Marieke C.; Protonotarios, Alexandros; Boven, Ludolf G.; Amat-Codina, Nuria; Groeneweg, Judith A.; Wilde, Arthur A.; Sobreira, Nara; Calkins, Hugh; Hauer, Richard N. W.; Jonkman, Marcel F.; McKenna, William J.; Elliott, Perry M.; Sinke, Richard J.; van den Berg, Maarten P.; Chelko, Stephen P.; James, Cynthia A.
- 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.
- Subjects
PLECTIN; CARDIOMYOPATHIES; DESMOPLAKIN; IMMUNOFLUORESCENCE; PATHOLOGICAL physiology; DIAGNOSIS
- Publication
PLoS ONE, 2018, Vol 13, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0203078