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Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.

Begay, RL; Graw, SL; Sinagra, G; Asimaki, A; Rowland, TJ; Slavov, DB; Gowan, K; Jones, KL; Brun, F; Merlo, M; et al. Begay, RL; Graw, SL; Sinagra, G; Asimaki, A; Rowland, TJ; Slavov, DB; Gowan, K; Jones, KL; Brun, F; Merlo, M; Miani, D; Sweet, M; Devaraj, K; Wartchow, EP; Gigli, M; Puggia, I; Salcedo, EE; Garrity, DM; Ambardekar, AV; Buttrick, P; Reece, TB; Bristow, MR; Saffitz, JE; Mestroni, L; Taylor, MRG (2018) Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures. JACC Clin Electrophysiol, 4 (4). pp. 504-514. ISSN 2405-5018 https://doi.org/10.1016/j.jacep.2017.12.003
SGUL Authors: Asimaki, Angeliki

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Abstract

OBJECTIVES: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype. BACKGROUND: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement. METHODS: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry. RESULTS: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa. CONCLUSIONS: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.

Item Type: Article
Additional Information: © 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Filamin C, arrhythmias, arrhythmogenic dilated cardiomyopathy, cardiovascular genetics, familial dilated cardiomyopathy, heart failure
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: JACC Clin Electrophysiol
ISSN: 2405-5018
Language: eng
Dates:
DateEvent
April 2018Published
2 February 2018Published Online
7 December 2017Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
R01 HL109209National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
HL116906National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 116906National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
1K23HI067915National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01HL109209National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
UL1 TR001082National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 30067491
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110422
Publisher's version: https://doi.org/10.1016/j.jacep.2017.12.003

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