دورية أكاديمية
shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele.
العنوان: | shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele. |
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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. |
References: | Thromb Haemost. 2020 Nov;120(11):1569-1579. (PMID: 32803740) EMBO Mol Med. 2018 Feb;10(2):239-253. (PMID: 29246969) Europace. 2013 Oct;15(10):1389-406. (PMID: 23994779) Retrovirology. 2006 Jan 06;3:2. (PMID: 16398936) Sci Adv. 2018 Mar 07;4(3):eaar2631. (PMID: 29532034) Nature. 2015 Oct 1;526(7571):68-74. (PMID: 26432245) Nat Genet. 1996 Jan;12(1):17-23. (PMID: 8528244) Neuron. 2012 Sep 6;75(5):779-85. (PMID: 22958819) J Biol Chem. 1999 Jul 23;274(30):21063-70. (PMID: 10409658) J Cardiol. 2019 May;73(5):343-350. (PMID: 30591322) J Am Coll Cardiol. 2011 Jan 4;57(1):51-9. (PMID: 21185501) Circulation. 1997 Sep 16;96(6):1733-6. (PMID: 9323054) Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3003-11. (PMID: 11087258) Open Heart. 2018 Dec 16;5(2):e000877. (PMID: 30613409) Science. 2013 Oct 4;342(6154):111-4. (PMID: 24092743) Cell Stem Cell. 2013 Jan 3;12(1):127-37. (PMID: 23168164) PLoS One. 2012;7(11):e49309. (PMID: 23145149) Physiol Genomics. 2020 Jul 1;52(7):293-303. (PMID: 32567507) Stem Cell Reports. 2015 Oct 13;5(4):582-96. (PMID: 26372632) Eur Heart J. 2012 Mar;33(6):714-23. (PMID: 22199116) J Cardiovasc Pharmacol Ther. 2014 Sep;19(5):426-38. (PMID: 24742766) Circulation. 2007 May 15;115(19):2481-9. (PMID: 17470695) Circulation. 2012 Apr 24;125(16):1988-96. (PMID: 22456477) Heart Rhythm. 2018 Oct;15(10):1566-1574. (PMID: 29857160) Curr Heart Fail Rep. 2020 Oct;17(5):234-246. (PMID: 32789749) Curr Probl Cardiol. 2008 Nov;33(11):629-94. (PMID: 18835466) Circulation. 2019 Aug 27;140(9):765-778. (PMID: 31315475) Circ Res. 2017 Aug 18;121(5):525-536. (PMID: 28620067) Channels (Austin). 2010 Jan-Feb;4(1):3-11. (PMID: 19934648) N Engl J Med. 1992 Sep 17;327(12):846-52. (PMID: 1508244) Curr Biol. 2009 May 12;19(9):774-8. (PMID: 19361997) Stem Cell Res Ther. 2015 Mar 19;6:39. (PMID: 25889101) Eur Heart J. 2014 Apr;35(16):1078-87. (PMID: 23470493) Circulation. 2009 Nov 3;120(18):1761-7. (PMID: 19841298) Biochem Biophys Res Commun. 2005 Apr 8;329(2):516-21. (PMID: 15737617) Circ Genom Precis Med. 2018 Nov;11(11):e002345. (PMID: 30571187) Circ J. 2014;78(12):2827-33. (PMID: 25274057) J Am Coll Cardiol. 2018 Apr 17;71(15):1663-1671. (PMID: 29650123) Circulation. 2021 Apr 6;143(14):1411-1425. (PMID: 33504163) Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1573-89. (PMID: 14656705) Circulation. 2021 Apr 13;143(15):1502-1512. (PMID: 33583186) Eur Heart J. 2015 Nov 1;36(41):2793-2867. (PMID: 26320108) Nat Methods. 2014 Aug;11(8):855-60. (PMID: 24930130) PLoS One. 2012;7(7):e40288. (PMID: 22815737) Heart Rhythm. 2013 Jan;10(1):128-36. (PMID: 23022675) Nat Rev Drug Discov. 2021 Mar;20(3):173-174. (PMID: 33495615) Arch Dis Child. 2015 Mar;100(3):279-82. (PMID: 25270334) Nucleic Acids Res. 2009 Dec;37(22):7560-9. (PMID: 19815667) J Cardiovasc Pharmacol. 2021 Mar 1;77(3):267-279. (PMID: 33229908) J Am Coll Cardiol. 2012 Sep 11;60(11):990-1000. (PMID: 22749309) Nat Rev Immunol. 2014 Jan;14(1):36-49. (PMID: 24362405) Circulation. 2000 Feb 15;101(6):616-23. (PMID: 10673253) Cardiovasc Res. 2005 Aug 15;67(3):487-97. (PMID: 15950200) Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2006-17. (PMID: 21890694) Clin Genet. 2019 Feb;95(2):199-209. (PMID: 30280378) PLoS One. 2013;8(4):e59494. (PMID: 23577066) Prog Biophys Mol Biol. 2016 Dec;122(3):202-214. (PMID: 27221779) Stem Cells Int. 2019 Mar 6;2019:7532657. (PMID: 30956674) Br J Pharmacol. 2017 Nov;174(21):3749-3765. (PMID: 27641943) J Control Release. 2015 Apr 10;203:1-15. (PMID: 25660205) Curr Protoc Hum Genet. 2016 Apr 01;89:8.16.1-8.16.23. (PMID: 27037489) Nucleic Acids Res. 2009 Apr;37(6):e45. (PMID: 19237396) Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1088-100. (PMID: 16565318) |
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 |
تدمد: | 1422-0067 |
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DOI: | 10.3390/ijms23074053 |