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PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.

Authors
  • van Kampen, Sebastiaan J1
  • Han, Su Ji1
  • van Ham, Willem B2
  • Kyriakopoulou, Eirini1
  • Stouthart, Elizabeth W1
  • Goversen, Birgit3
  • Monshouwer-Kloots, Jantine1
  • Perini, Ilaria1
  • de Ruiter, Hesther1
  • van der Kraak, Petra4
  • Vink, Aryan4
  • van Laake, Linda W5
  • Groeneweg, Judith A5
  • de Boer, Teun P2
  • Tsui, Hoyee1
  • Boogerd, Cornelis J1
  • van Veen, Toon A B2
  • van Rooij, Eva6
  • 1 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. , (Netherlands)
  • 2 Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 3 Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical Center, the Netherlands. , (Netherlands)
  • 4 Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 5 Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. , (Netherlands)
  • 6 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: [email protected]. , (Netherlands)
Type
Published Article
Journal
Stem Cell Reports
Publisher
Elsevier
Publication Date
Mar 14, 2023
Volume
18
Issue
3
Pages
749–764
Identifiers
DOI: 10.1016/j.stemcr.2023.01.015
PMID: 36868229
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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