EP News: Basic and Translational

Abstract

Cardiac conduction system (CCS) disease is common with significant morbidity and mortality. Recent genome-wide association studies (GWAS) have identified numerous loci associated with adult human CCS function, including TBX5 and SCN5A. Arnolds et al (J Clin Invest 2012;122:2509, PMID 22728936) found that the deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the atrioventricular bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death. However, key mediators of fast conduction, including Nav1.5 (which is encoded by Scn5a) and connexin 40, demonstrated Tbx5-dependent expression in the VCS. The authors identified a TBX5-responsive enhancer downstream of Scn5a sufficient to drive VCS expression in vivo, dependent on canonical T-box binding sites. These results establish a direct molecular link between Tbx5 and Scn5a and elucidate a hierarchy between human GWAS loci that affects function of the mature VCS, establishing a paradigm for understanding the molecular pathology of CCS disease.