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

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