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Transl. Med."],"published-print":{"date-parts":[[2026,4,29]]},"abstract":"\n Dipeptidyl aminopeptidase\u2013like protein 6 (DPP6) is a subunit of the K\n v<\/jats:sub>\n 4 channels that carry the transient-outward current (\n I<\/jats:italic>\n to<\/jats:sub>\n ) in cardiac Purkinje cells (PCs) and ventricular myocytes (VMs).\n DPP6<\/jats:italic>\n genetic variants have been linked to severe arrhythmia syndromes. Given the influence of other\n I<\/jats:italic>\n to<\/jats:sub>\n subunits on the Na\n v<\/jats:sub>\n 1.5-mediated cardiac sodium current (\n I<\/jats:italic>\n Na<\/jats:sub>\n ), we examined whether DPP6 regulates both\n I<\/jats:italic>\n to<\/jats:sub>\n and\n I<\/jats:italic>\n Na<\/jats:sub>\n . We explored the impact of the\n DPP6<\/jats:italic>\n 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\n v<\/jats:sub>\n 1.5. Functionally, DPP6 reduced\n I<\/jats:italic>\n Na<\/jats:sub>\n and increased\n I<\/jats:italic>\n to<\/jats:sub>\n density in transfected Chinese hamster ovary cells.\n DPP6<\/jats:italic>\n variants linked to LQTS and JWSs led to a hypo- and hyperinhibition of\n I<\/jats:italic>\n Na<\/jats:sub>\n , respectively. Conversely,\n I<\/jats:italic>\n to<\/jats:sub>\n was increased by the JWS variants and decreased by the LQTS variants coexpressed with PC (but not VM)\n I<\/jats:italic>\n to<\/jats:sub>\n subunits. These findings were validated in human induced pluripotent stem cell\u2013derived cardiomyocytes. In silico modeling of\n I<\/jats:italic>\n Na<\/jats:sub>\n and\n I<\/jats:italic>\n to<\/jats:sub>\n 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\n DPP6<\/jats:italic>\n c.821G>A index patient versus right ventricular outflow tract delayed activation of a\n DPP6<\/jats:italic>\n c.2252C>T carrier. In conclusion,\n DPP6<\/jats:italic>\n variants play an important role in the mutually antagonistic regulation of\n I<\/jats:italic>\n Na<\/jats:sub>\n and\n I<\/jats:italic>\n to<\/jats:sub>\n , contributing to cardiac electrophysiology and arrhythmogenesis.\n <\/jats:p>","DOI":"10.1126\/scitranslmed.adn3180","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:59:07Z","timestamp":1777485547000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Dipeptidyl aminopeptidase\u2013like protein 6 regulates the\n I<\/i>\n Na<\/sub>\n -\n I<\/i>\n to<\/sub>\n balance influencing cardiac electrophysiology and arrhythmogenesis"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9266-5328","authenticated-orcid":true,"given":"Alberto","family":"Rossetti","sequence":"first","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8881-5498","authenticated-orcid":true,"given":"Job","family":"Stoks","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."},{"name":"Department of Advanced Computing Sciences, Maastricht University, 6229 GS Maastricht, Netherlands."},{"name":"Faculty of Medicine and Life Sciences, Hasselt University, 3950 Diepenbeek, Belgium."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5508-7129","authenticated-orcid":true,"given":"Roel L. H. M. G.","family":"Sp\u00e4tjens","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1895-4538","authenticated-orcid":true,"given":"Susanne","family":"K\u00e4mmerer","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0269-3499","authenticated-orcid":true,"given":"Jason","family":"Bayer","sequence":"additional","affiliation":[{"name":"IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Universit\u00e9, 3360 Pessac-Bordeaux, France."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaofei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgios","family":"Kosmidis","sequence":"additional","affiliation":[{"name":"Ncardia B.V., 2333 CH Leiden, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Firneburg","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4978-976X","authenticated-orcid":true,"given":"Sandrine R. M.","family":"Seyen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4278-0132","authenticated-orcid":true,"given":"Rachel M. A.","family":"ter Bekke","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4088-8183","authenticated-orcid":true,"given":"Apollonia T. J. M.","family":"Helderman-van den Enden","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Center+, 6229 HX Maastricht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3854-6749","authenticated-orcid":true,"given":"J. Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0528-0852","authenticated-orcid":true,"given":"Arthur A. 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