Please use this identifier to cite or link to this item: https://doi.org/10.1186/s13287-015-0027-z
Title: 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
Authors: Ma D. 
Wei H. 
Lu J.
Huang D.
Liu Z.
Loh L.J.
Islam O. 
Liew R. 
Shim W. 
Cook S.A. 
Issue Date: 2015
Publisher: BioMed Central Ltd.
Citation: Ma D., Wei H., Lu J., Huang D., Liu Z., Loh L.J., Islam O., Liew R., Shim W., Cook S.A. (2015). 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. Stem Cell Research and Therapy 6 (1) : 39. ScholarBank@NUS Repository. https://doi.org/10.1186/s13287-015-0027-z
Abstract: Introduction: Type 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. Methods: A 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. Results: Compared 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 ñ 0.02 vs. 0.92 ñ 0.21, P < 0.05) and prolonged action potential duration (APD) (APD 50 and APD90: 603.9 ñ 39.2 vs. 319.3 ñ 13.8 ms, P < 0.005; and 671.0 ñ 41.1 vs. 372.9 ñ 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. Conclusions: From 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. ? 2015 Ma et al.; licensee BioMed Central.
Source Title: Stem Cell Research and Therapy
URI: http://scholarbank.nus.edu.sg/handle/10635/150849
ISSN: 17576512
DOI: 10.1186/s13287-015-0027-z
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