An emerging role for DPP6: reciprocal regulation of INa-Ito and implications for arrhythmogenesis

Abstract

Abstract Background Since the association of a chromosomal risk haplotype harboring dipeptidyl peptidase-like protein-6 (DPP6) to familial idiopathic ventricular fibrillation (iVF), a growing number of DPP6 missense variants has been reported in patients with ventricular tachyarrhythmias. The mechanisms underlying DPP6 mediated-arrhythmogenesis are not yet fully elucidated. DPP6 is a subunit of the transient outward potassium (Ito) channel complex in Purkinje cells (PC) and ventricular myocytes (VM). Purpose Since other Ito-channel subunits (Navβ1, KChIP2, KCNE4 and DPP10) are also known to antagonize INa, we examined whether DPP6 could play a broader role in the inter-regulation of Kv4.3 and Nav1.5 channels. We identified two novel DPP6 variants (p.Arg274His and p.His213Tyr), each segregating in families with QT/QU prolongation. DPP6 p.Arg274His carriers suffered from iVF, ectopic beats from the conduction system, and mitral valve prolapse. Other DPP6 variants (p.Ala751Val identified in this study; p.Gln526His and DPP6-T p.His332Arg published) are associated with Brugada syndrome (BrS). We hypothesized that DPP6 has opposing effects on INa and Ito displaying a reciprocal regulation of these currents. Methods and results First, we determined the effect of the DPP6 variants on INa and Ito in transfected CHO cells. Ito density was significantly reduced only when PC subunits were co-expressed with the DPP6 p.Arg274His or p.His213Tyr variants. Indeed, DPP6 modulates Nav1.5 channels in CHO cells by reducing INa Peak and INa Late, whereas DPP6 mutants p.Arg274His or p.His213Tyr resulted in an increase of both components compared to WT. Co-immunoprecipitation experiments in human endocardium confirmed an interaction between DPP6 and Nav1.5 channels. Computing of mutant DPP6-driven Ito-INa changes in a published human PC model led to significant prolongation of the action potential duration, mainly caused by increased INa Late. On the other hand, the DPP6 p.Gln526His and p.Ala751Val variants, linked to BrS, led to a decreased INa Peak compared to the WT, while there was a tendency towards increased Ito density in both PC and VM molecular setups. DPP6 (p.Arg274His and p.Ala751Val) transfection experiments in hiPSC cardiomyocytes, expressing endogenous INa and Ito, confirmed the reciprocal results obtained in CHO cells. Conclusions DPP6 regulates INa and Ito in a reciprocal manner. The cardiac phenotype of DPP6 variants could encompass a spectrum between two opposite poles: 1) QT/QU prolongation by DPP6 variants causing loss of Ito and gain of INa, like p.Arg274His and p.His213Tyr versus 2) BrS by DPP6 variants leading to gain of Ito and loss of INa, like p.Gln526His and p.Ala751Val. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): ESC Personal research grant, obtained in 2019