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ResearchIn-Press PreviewCardiologyDevelopmentGenetics Open Access | 10.1172/JCI207010

PITX2 missense coding variant expression in mice reveals direct function in atrial fibrillation

Jeffrey D. Steimle,1 Yue Yuan,2 Shaohai Fang,3 Vaibhav Deshmukh,2 Christine Rodriguez,4 Fansen Meng,5 Taotao Tan,1 Md. Abul Hassan Samee,1 Yun Huang,3 Na Li,2 and James F. Martin1

1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

Find articles by Tan, T. in: PubMed | Google Scholar

1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

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1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

Find articles by Huang, Y. in: PubMed | Google Scholar

1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

Find articles by Li, N. in: PubMed | Google Scholar

1Department of Integrative Physiology and The Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

2Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, United States of America

3Institute of Biosciences and Technology, Texas A&M University, Houston, United States of America

4Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States of America

5Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, United States of America

Find articles by Martin, J. in: PubMed | Google Scholar |

Published September 29, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI207010.
Copyright © 2026, Steimle et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 29, 2026 - Version history
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Abstract

Atrial fibrillation (AF) is the most common sustained human cardiac arrhythmia and linked to a drastic increase in stroke and heart failure risk. While sequence variations in the PITX2 non-coding region are the strongest genetic signature of AF risk, the direct role of PITX2 in AF remains a topic of debate. Here, we generated a mouse model (Pitx2Pro41Ser) of a human PITX2 coding variant linked to increased AF risk in the Finnish population. The Pitx2Pro41Ser mice exhibit near-complete penetrance of pacing-induced AF, and transcriptional profiling indicates that Pitx2Pro41Ser is a loss-of-function mutation. In vivo cleavage under targets and tagmentation (CUT&Tag) reveals that PITX2 acts as a transcriptional repressor in developing left atrial cardiomyocytes independent of DNA methylation. Ectopic Pitx2 expression in postnatal right atrial cardiomyocytes via adeno-associated virus (AAV) delivery or genetic overexpression represses right atrial genes and induces a left atrial transcriptome, revealing unexpected plasticity of postnatal atrial cardiomyocytes. Strikingly, delivery of Pitx2 AAV into Pitx2Pro41Ser mice rescues AF inducibility uncovering a direct link between PITX2 activity and AF susceptibility.

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Version history
  • Version 1 (September 29, 2026): In-Press Preview
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