Year: 2018
Type: article
Study design: Observational Study
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.
Source: PLoS ONE
Authors: 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
Institutions: University Medical Center Groningen, University of Groningen, Netherlands Heart Institute, University College London, Johns Hopkins University, Johns Hopkins Medicine, University Medical Center Utrecht, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam UMC Location University of Amsterdam, Medical University of South Carolina
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Johns Hopkins University, Baylor-Hopkins Center for Mendelian Genomics, National Institute for Health and Care Research, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Intellectual and Developmental Disabilities Research Centers 2020, NIHR Senior Investigator Award, G5425049328, Baylor Johns Hopkins Center for Mendelian Genetics, Institute for Clinical and Translational Research, aritmogene cardiomyopathie: naar een risico-inschatting voor een erfelijke, ernstige, levensbedreigende hartspierziekte
OpenAlex ID: W2889533064