Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.
Lee, Jaecheol , Termglinchan, Vittavat , Diecke, Sebastian , Itzhaki, Ilanit , Lam, Chi Keung , Garg, Priyanka , Lau, Edward , Greenhaw, Matthew , Seeger, Timon , Wu, Haodi , Zhang, Joe Z , Chen, Xingqi , Gil, Isaac Perea , Ameen, Mohamed , Sallam, Karim , Rhee, June-Wha , Churko, Jared M , Chaudhary, Rinkal , Chour, Tony , Wang, Paul J , Snyder, Michael P , Chang, Howard Y , Karakikes, Ioannis , Wu, Joseph C
Publication Details
- Journal: Nature
- Volume: 572 (7769 )
- Pages: 335-340
- Published: Aug 2019
- Type: Journal Article
Abstract
Lamin A/C (LMNA) is one of the most frequently mutated genes associated
with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-beta (PDGFRB) as a potential therapeutic target.
Links & Resources
Added: January 15, 2026 | Updated: January 15, 2026