Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy


  • J. Lee
  • V. Termglinchan
  • S. Diecke
  • I. Itzhaki
  • C.K. Lam
  • P. Garg
  • E. Lau
  • M. Greenhaw
  • T. Seeger
  • H. Wu
  • J.Z Zhang
  • X. Chen
  • I.P. Gil
  • M. Ameen
  • K. Sallam
  • J.W. Rhee
  • J.M. Churko
  • R. Chaudhary
  • T. Chour
  • P.J. Wang
  • M.P. Snyder
  • H.Y. Chang
  • I. Karakikes
  • J.C. Wu


  • Nature


  • Nature 572 (7769): 335-340


  • 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-β (PDGFRB) as a potential therapeutic target.