Functional Role of the L396R Mutation of Tks5 Identified by an Exome-Wide Association Study in Atrial Fibrillation
Open Access
- 25 November 2020
- journal article
- research article
- Published by Japanese Circulation Society in Circulation Journal
- Vol. 84 (12), 2148-2157
- https://doi.org/10.1253/circj.cj-20-0101
Abstract
Background:Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, the current treatment strategies for AF have limited efficacy. Thus, a better understanding of the mechanisms underlying AF is important for future therapeutic strategy. A previous study (Exome-Wide Association Study (ExWAS)) identified a rare variant, rs202011870 (MAF=0.00036, GenomAD), which is highly associated with AF (OR=3.617, PMethods and Results:The association of rs202011870 with AF was examined in 3,378 participants (641 control and 2,737 AF cases) from 4 independent cohorts by using an Invader assay. Consequences of rs202011870 in migration ability, podosome formation, and expression of inflammation-related molecules in macrophages were examined using RAW264.7 cells with a trans-well assay, immunocytochemistry, and qPCR assay. Validation of the association of rs202011870 with AF was successful. In vitro studies showed that RAW264.7 cells with L396R-Tks5 increased trans-well migration ability, and enhanced podosome formation. RAW264.7 cells with L396R-Tks5 also increased the expression of several inflammatory cytokines and inflammation-related molecules. Conclusions:L396R mutation in Tks5 associated with AF enhances migration of macrophages and their inflammatory features, resulting in enhanced susceptibility to AF.Keywords
This publication has 22 references indexed in Scilit:
- Worldwide Epidemiology of Atrial FibrillationJournal of the American College of Cardiology, 2014
- Cell migration and invasion in human disease: the Tks adaptor proteinsBiochemical Society Transactions, 2012
- The podosome marker protein Tks5 regulates macrophage invasive behaviorCytoskeleton, 2011
- Podosome rings generate forces that drive saltatory osteoclast migrationMolecular Biology of the Cell, 2011
- The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and functionNature Reviews Molecular Cell Biology, 2011
- Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathwayOncogene, 2009
- Cell Biology: Watching the First Steps of Podosome FormationCurrent Biology, 2008
- The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cellsCancer Cell, 2005
- Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivationJournal of Molecular and Cellular Cardiology, 2004
- Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarctionNature Genetics, 2002