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We aimed to determine the role of ion channels controlling cardiac excitability in the mechanisms of arrhythmias in DMD patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      To test whether dystrophin mutations lead to defective cardiac Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5\u2013Kir2.1 channelosomes and arrhythmias, we generated iPSC-CMs from two hemizygous DMD males, a heterozygous female, and two unrelated control males. We conducted studies including confocal microscopy, protein expression analysis, patch-clamping, non-viral piggy-bac gene expression, optical mapping and contractility assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Two patients had abnormal ECGs with frequent runs of ventricular tachycardia. iPSC-CMs from all DMD patients showed abnormal action potential profiles, slowed conduction velocities, and reduced sodium (I\n                      <jats:sub>Na<\/jats:sub>\n                      ) and inward rectifier potassium (I\n                      <jats:sub>K1<\/jats:sub>\n                      ) currents. Membrane Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5 and Kir2.1 protein levels were reduced in hemizygous DMD iPSC-CMs but not in heterozygous iPSC-CMs. Remarkably, transfecting just one component of the dystrophin protein complex (\u03b11-syntrophin) in hemizygous iPSC-CMs from one patient restored channelosome function, I\n                      <jats:sub>Na<\/jats:sub>\n                      and I\n                      <jats:sub>K1<\/jats:sub>\n                      densities, and action potential profile in single cells. In addition, \u03b11-syntrophin expression restored impulse conduction and contractility and prevented reentrant arrhythmias in hiPSC-CM monolayers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      We provide the first demonstration that iPSC-CMs reprogrammed from skin fibroblasts of DMD patients with cardiomyopathy have a dysfunction of the Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5\u2013Kir2.1 channelosome, with consequent reduction of cardiac excitability and conduction. Altogether, iPSC-CMs from patients with DMD cardiomyopathy have a Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5\u2013Kir2.1 channelosome dysfunction, which can be rescued by the scaffolding protein \u03b11-syntrophin to restore excitability and prevent arrhythmias.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>\n                      Supported by National Institutes of Health R01 HL122352 grant; \u2018la Caixa\u2019 Banking Foundation (HR18-00304); Fundaci\u00f3n La Marat\u00f3 TV3:\n                      <jats:italic>Ayudas a la investigaci\u00f3n en enfermedades raras<\/jats:italic>\n                      2020 (LA MARATO-2020); Instituto de Salud Carlos III\/FEDER\/FSE; Horizon 2020 - Research and Innovation Framework Programme GA-965286 to JJ; the CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovaci\u00f3n (MCIN) and the Pro CNIC Foundation), and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN\/AEI\/10.13039\/501100011033). American Heart Association postdoctoral fellowship 19POST34380706s to JVEN. Israel Science Foundation to OB and MA [824\/19]. Rappaport grant [01012020RI]; and Niedersachsen Foundation [ZN3452] to OB; US-Israel Binational Science Foundation (BSF) to OB and TH [2019039]; Dr. Bernard Lublin Donation to OB; and The Duchenne Parent Project Netherlands (DPPNL 2029771) to OB. National Institutes of Health R01 AR068428 to DM and US-Israel Binational Science Foundation Grant [2013032] to DM and OB.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.76576","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T03:15:19Z","timestamp":1654658119000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.76576","source":"Crossref","is-referenced-by-count":27,"title":["SNTA1 gene rescues ion channel function and is antiarrhythmic in cardiomyocytes derived from induced pluripotent stem cells from muscular dystrophy patients"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5134-491X","authenticated-orcid":true,"given":"Eric N","family":"Jimenez-Vazquez","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Internal Medicine and Molecular and Integrative Physiology, Center for 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