Rossetti_2026_Sci.Transl.Med_18_eadn3180

Dipeptidyl aminopeptidase-like protein 6 (DPP6) is a subunit of the K(v)4 channels that carry the transient-outward current (I(to)) in cardiac Purkinje cells (PCs) and ventricular myocytes (VMs). DPP6 genetic variants have been linked to severe arrhythmia syndromes. Given the influence of other I(to) subunits on the Na(v)1.5-mediated cardiac sodium current (I(Na)), we examined whether DPP6 regulates both I(to) and I(Na). We explored the impact of the DPP6 missense variants c.821G>A and c.637C>T, segregating in families with long-QT syndrome (LQTS), and c.2252C>T and c.1578G>C, associated with J-wave syndromes (JWSs) and unexplained syncope. In human and mouse heart slices, DPP6 localized within 40 nanometers of Na(v)1.5. Functionally, DPP6 reduced I(Na) and increased I(to) density in transfected Chinese hamster ovary cells. DPP6 variants linked to LQTS and JWSs led to a hypo- and hyperinhibition of I(Na), respectively. Conversely, I(to) was increased by the JWS variants and decreased by the LQTS variants coexpressed with PC (but not VM) I(to) subunits. These findings were validated in human induced pluripotent stem cell-derived cardiomyocytes. In silico modeling of I(Na) and I(to) data into PC and VM single-cell action potentials, subsequently integrated in two-dimensional tissue simulations, produced steep repolarization gradients for LQTS-c.821G>A versus slowed conduction for JWS-c.2252C>T. Noninvasive electrocardiographic imaging, used for advanced clinical phenotyping, showed dispersed and prolonged repolarization in the DPP6 c.821G>A index patient versus right ventricular outflow tract delayed activation of a DPP6 c.2252C>T carrier. In conclusion, DPP6 variants play an important role in the mutually antagonistic regulation of I(Na) and I(to), contributing to cardiac electrophysiology and arrhythmogenesis.