ArticleStem cell research & therapy2015
Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patient-specific induced pluripotent stem cell-derived cardiomyocytes.
Article in Stem cell research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 94 citations in OpenAlex.
- Article
- The role of iPSC research for insight into inherited arrhythmia conditions.Heart rhythm · 2025Review
- Unlocking the therapeutic potential: odyssey of induced pluripotent stem cells in precision cell therapies.International journal of surgery (London, England) · 2024Review
- Stem cell-derived cardiomyocyte heterogeneity confounds electrophysiological insights.The Journal of physiology · 2024Review
- Advances in induced pluripotent stem cell-derived cardiac myocytes: technological breakthroughs, key discoveries and new applications.The Journal of physiology · 2024Review
- Using induced pluripotent stem cells for drug discovery in arrhythmias.Expert opinion on drug discovery · 2024Review
- Pairwise biosynthesis of ion channels stabilizes excitability and mitigates arrhythmias.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention.PNAS nexus · 2023Article
- IBiomedicines · 2023Article
- iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development.Biomedicines · 2023Review
- Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.Expert reviews in molecular medicine · 2023Review
- Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.Nature communications · 2022Article
- PKC regulation of ion channels: The involvement of PIPThe Journal of biological chemistry · 2022Review
- Review
- shRNAs Targeting a CommonInternational journal of molecular sciences · 2022Article
- Pharmacological rescue of specific long QT variants of KCNQ1/KCNE1 channels.Frontiers in physiology · 2022Article
- Deciphering Common Long QT Syndrome Using CRISPR/Cas9 in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.Frontiers in cardiovascular medicine · 2022Review
- Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
introductionType 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of KCNQ1. Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs). With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes.
methodsA LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs.
resultsCompared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33±0.02 vs. 0.92±0.21, P<0.05) and prolonged action potential duration (APD) (APD 50 and APD90: 603.9±39.2 vs. 319.3±13.8 ms, P<0.005; and 671.0±41.1 vs. 372.9±14.2 ms, P<0.005). ML277, a small molecule recently identified to selectively activate KV7.1, reversed the decreased IKs and partially restored APDs in patient hiPSC-CMs.
conclusionsFrom a LQT1 patient carrying a novel heterozygous exon7 deletion mutation of KCNQ1, we generated hiPSC-CMs that faithfully recapitulated the LQT1 phenotypes that are likely associated with haploinsufficiency and trafficking defect of KCNQ1/Kv7.1. The small molecule ML277 restored IKs function in hiPSC-CMs and could have therapeutic value for LQT1 patients.
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