Key result
Pitx2 Pro41Ser mutation drives pacing-induced AF, increasing penetrance to 100% vs. 22% in wild-type mice.
Why the study?
The direct role of PITX2 coding variants in atrial fibrillation susceptibility remains debated despite strong genetic associations in non-coding regions.
Absolute Event Rate: 100% vs 22%
p-value: p=1.6e-7
The Pitx2 Pro41Ser mutation acts as a loss-of-function allele that increases atrial fibrillation susceptibility in mice, which can be rescued by AAV-mediated PITX2 gene therapy.
Establishes Pitx2 loss-of-function as sufficient for atrial fibrillation susceptibility in mice; leaves open translation to human gene therapy.
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 ( Pitx2 Pro41Ser ) of a human PITX2 coding variant linked to increased AF risk in the Finnish population. The Pitx2 Pro41Ser mice exhibit near-complete penetrance of pacing-induced AF, and transcriptional profiling indicates that Pitx2 Pro41Ser 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 Pitx2 Pro41Ser mice rescues AF inducibility uncovering a direct link between PITX2 activity and AF susceptibility.
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Steimle et al. (2026) studied Atrial Fibrillation (n=74). Pitx2Pro41Ser allele vs. Wild-type littermates was evaluated on Pacing-induced arrhythmias (p=1.6e-7).
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