{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:44:05Z","timestamp":1792521845091,"version":"4.5.0"},"reference-count":63,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T00:00:00Z","timestamp":1649203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DCVA ARENA-PRIME Young Talent program","award":["-"],"award-info":[{"award-number":["-"]}]},{"DOI":"10.13039\/501100001826","name":"Netherlands Organisation for Health Research and Development","doi-asserted-by":"publisher","award":["VENI 91616150"],"award-info":[{"award-number":["VENI 91616150"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1. Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1-encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a common variant can shift the balance towards increased incorporation of the wild-type allele to alleviate the disease in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We identified the single nucleotide polymorphisms (SNP) rs1057128 (G\/A) in KCNQ1, with a heterozygosity of 27% in the European population. Next, we determined allele-specificity of short-hairpin RNAs (shRNAs) targeting either allele of this SNP in hiPSC-CMs that carry an LQT1 mutation. Our shRNAs downregulated 60% of the A allele and 40% of the G allele without affecting the non-targeted allele. Suppression of the mutant KCNQ1 allele by 60% decreased the occurrence of arrhythmic events in hiPSC-CMs measured by a voltage-sensitive reporter, while suppression of the wild-type allele increased the occurrence of arrhythmic events. Furthermore, computer simulations based on another LQT1 mutation revealed that 60% suppression of the mutant KCNQ1 allele shortens the prolonged action potential in an adult cardiomyocyte model. We conclude that allele-specific inhibition of a mutant KCNQ1 allele by targeting a common variant may alleviate the disease. This novel approach avoids the need to design shRNAs to target every single mutation and opens up the exciting possibility of treating multiple LQT1-causing mutations with only two shRNAs.<\/jats:p>","DOI":"10.3390\/ijms23074053","type":"journal-article","created":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T16:21:30Z","timestamp":1649262090000},"page":"4053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele"],"prefix":"10.3390","volume":"23","author":[{"given":"Luc\u00eda","family":"C\u00f3cera-Ortega","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-0869","authenticated-orcid":false,"given":"Ronald","family":"Wilders","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina C.","family":"Kamps","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Fabrizi","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irit","family":"Huber","sequence":"additional","affiliation":[{"name":"The Sohnis Family Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion\u2014Israel Institute of Technology, Haifa 3109601, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingeborg","family":"van der Made","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk","family":"van den Bout","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan K.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior","family":"Gepstein","sequence":"additional","affiliation":[{"name":"The Sohnis Family Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion\u2014Israel Institute of Technology, Haifa 3109601, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-834X","authenticated-orcid":false,"given":"Arie O.","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yigal M.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8030-8894","authenticated-orcid":false,"given":"Anke J.","family":"Tijsen","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1161\/CIRCULATIONAHA.109.863209","article-title":"Prevalence of the congenital long-QT syndrome","volume":"120","author":"Schwartz","year":"2009","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cpcardiol.2008.07.002","article-title":"Long QT Syndrome","volume":"33","author":"Goldenberg","year":"2008","journal-title":"Curr. 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