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RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy.

Hall, CL; Gurha, P; Sabater-Molina, M; Asimaki, A; Futema, M; Lovering, RC; Suárez, MP; Aguilera, B; Molina, P; Zorio, E; et al. Hall, CL; Gurha, P; Sabater-Molina, M; Asimaki, A; Futema, M; Lovering, RC; Suárez, MP; Aguilera, B; Molina, P; Zorio, E; Coarfa, C; Robertson, MJ; Cheedipudi, SM; Ng, K-E; Delaney, P; Hernández, JP; Pastor, F; Gimeno, JR; McKenna, WJ; Marian, AJ; Syrris, P (2020) RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy. Int J Cardiol, 302. pp. 124-130. ISSN 1874-1754 https://doi.org/10.1016/j.ijcard.2019.12.002
SGUL Authors: Asimaki, Angeliki

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Abstract

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for dysregulated biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM.

Item Type: Article
Additional Information: © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Arrhythmogenic cardiomyopathy, Filamin C, Focal adhesion pathway, Integrin linked kinase pathway, RNA sequencing, 1102 Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Int J Cardiol
ISSN: 1874-1754
Language: eng
Dates:
DateEvent
1 March 2020Published
6 December 2019Published Online
2 December 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
14CVD03Fondation Leducqhttp://dx.doi.org/10.13039/501100001674
R01 HL088498National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
1R01HL132401National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
PI14/01477Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PI18/01582Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PT17/0015/0043Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PI14/01676Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PI18/01231Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PT17/0015/0038Instituto de Salud Carlos IIIhttp://dx.doi.org/10.13039/501100004587
PubMed ID: 31843279
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111525
Publisher's version: https://doi.org/10.1016/j.ijcard.2019.12.002

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