PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

Sebastiaan J van Kampen, Su Ji Han, Willem B van Ham, Eirini Kyriakopoulou, Elizabeth W Stouthart, Birgit Goversen, Jantine Monshouwer-Kloots, Ilaria Perini, Hesther de Ruiter, Petra van der Kraak, Aryan Vink, Linda W van Laake, Judith A Groeneweg, Teun P de Boer, Hoyee Tsui, Cornelis J Boogerd, Toon A B van Veen, Eva van Rooij

Research output: Contribution to journal/periodicalArticleScientificpeer-review


Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.

Original languageEnglish
Pages (from-to)749-764
Number of pages16
JournalStem Cell Reports
Issue number3
Publication statusPublished - 14 Mar 2023


  • Humans
  • Myocytes, Cardiac/metabolism
  • Connexin 43/genetics
  • Desmoplakins/genetics
  • Induced Pluripotent Stem Cells/metabolism
  • Mutation
  • Cardiomyopathies


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