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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0027-z) contains supplementary material, which is available to authorized users.
Highlights
Type 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of potassium channel (KCNQ1)
type 1 long QT syndrome (LQT1) patient-specific human induced pluripotent stem cell (hiPSC)-CMs express reduced wild type (WT) KCNQ1 accompanied by alternative transcriptions skipping exon 7 and exon 7 plus exon 8 hiPSCs were differentiated into hiPSC-CMs
In LQT1 patient hiPSCCMs, we found that the WT α-subunit of Kv7.1 is the predominant form, suggesting that the heterozygous deletion of exon 7 leads to haploinsufficiency associated with reduced slowly activating delayed rectifier potassium channel (IKs) currents and shortened action potential duration (APD)
Summary
Type 1 long QT syndrome (LQT1) is a common type of cardiac channelopathy associated with loss-of-function mutations of KCNQ1. 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. The recent breakthrough in generating human induced pluripotent stem cells (hiPSCs) from postnatal humans and their ability to be differentiated into functional cardiomyocytes (hiPSC-CMs) have opened a new page in the study of inherited cardiac diseases such as LQTS. Type 1 long QT syndrome (LQT1) is the most common subtype of LQTS (~40% of all LQTS) that is associated with loss of function of the slowly activating delayed rectifier potassium channel (IKs) in cardiomyocytes [5,6,7]. The exon 6 to exon 7 junction of KCNQ1 represents a splicing mutation hotspot and contains several splicing mutations [8,9,10,11]
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