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shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele.

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العنوان: shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele.
المؤلفون: Cócera-Ortega L; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Wilders R; Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Kamps SC; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Fabrizi B; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Huber I; The Sohnis Family Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 3109601, Israel., van der Made I; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., van den Bout A; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., de Vries DK; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Gepstein L; The Sohnis Family Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 3109601, Israel., Verkerk AO; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.; Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Pinto YM; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands., Tijsen AJ; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2022 Apr 06; Vol. 23 (7). Date of Electronic Publication: 2022 Apr 06.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: KCNQ1 Potassium Channel*/genetics , KCNQ1 Potassium Channel*/metabolism , Romano-Ward Syndrome*/genetics, Adult ; Alleles ; Humans ; RNA, Small Interfering ; Severity of Illness Index
مستخلص: 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.
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معلومات مُعتمدة: DCVA ARENA-PRIME Young Talent program; VENI 91616150 Netherlands Organisation for Health Research and Development
فهرسة مساهمة: Keywords: RNA interference; arrhythmia; gene therapy; hiPSC-cardiomyocytes; long-QT syndrome type 1
المشرفين على المادة: 0 (KCNQ1 Potassium Channel)
0 (KCNQ1 protein, human)
0 (RNA, Small Interfering)
تواريخ الأحداث: Date Created: 20220412 Date Completed: 20220413 Latest Revision: 20220415
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9000197
DOI: 10.3390/ijms23074053
PMID: 35409410
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms23074053