TBX5-p.G125R postnatally deregulates pacemaker cardiomyocyte state and function.
Heterozygosity for the pathogenic missense TBX5 (T-box transcription factor 5) variant p.G125R, identified in members of a family presenting with atypical Holt-Oram syndrome, is associated with supraventricular arrhythmias, including atrial fibrillation and disrupted sinus rhythm. Tbx5+/G125R mice recapitulated major aspects of the patient phenotype, including increased susceptibility for atrial arrhythmias, and revealed deregulation of the adult atrial cardiomyocyte transcriptional regulatory network and epigenetic state. Because TBX5 has also been implicated in the development and function of the sinus node and atria, and both patients and Tbx5+/G125R mice present with indications for sinus node dysfunction, we explored the impact of TBX5-p.G125R on gene expression in the fetal and adult sinus node and atria using spatial transcriptomics. We found that TBX5-p.G125R-mediated transcriptional alterations in the atria are initiated prior to birth, culminating in atrial arrhythmias in adult mice, while prenatal sinus node development and transcriptome were largely unaffected. However, TBX5-p.G125R induces a transcriptional state change in adult sinus node pacemaker cardiomyocytes, modifying pacemaker electrophysiology and disrupting intrinsic sinus node function. We conclude that alterations driven by TBX5-p.G125R in the transcriptional state of the postnatal sinus node contribute to sinus node dysfunction and atrial arrhythmias in adult Tbx5+/G125R mice. This emphasizes the critical role of TBX5 in maintaining pacemaker cardiomyocyte state and function.