4.6 Article

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

期刊

INTERNATIONAL JOURNAL OF CARDIOLOGY
卷 302, 期 -, 页码 124-130

出版社

ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2019.12.002

关键词

Arrhythmogenic cardiomyopathy; RNA sequencing; Filamin C; Focal adhesion pathway; Integrin linked kinase pathway

资金

  1. Fondation Leducq Transatlantic Networks of Excellence Program grant [14CVD03]
  2. NIHR University College London Hospitals Biomedical Research Centre, UK
  3. National Institutes of Health, National Heart, Lung and Blood Institute (NHLBI) [R01 HL088498, 1R01HL132401]
  4. Ewing Halsell Foundation
  5. George and Mary Josephine Hamman Foundation
  6. TexGen Fund from Greater Houston Community Foundation
  7. Plan Estatal de I+D+I 2013-2016 - European Regional Development Fund (FEDER) A way of making Europe, Instituto de Salud Carlos III, Spain [PI14/01477, PI18/01582, PT17/0015/0043, PI14/01676, PI18/01231, PT17/0015/0038]

向作者/读者索取更多资源

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. (C) 2019 The Authors. Published by Elsevier B.V.

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