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.

Autor: Ma D; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. ma.dongrui@nhcs.com.sg., Wei H; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. wei.he.ming@nhcs.com.sg.; Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857, Singapore. wei.he.ming@nhcs.com.sg., Lu J; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. lujun1986@hotmail.com., Huang D; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. huangdou1220@gmail.com., Liu Z; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. liu.zhenfeng@nhcs.com.sg., Loh LJ; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. loh.li.jun@nhcs.com.sg., Islam O; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. md.omedul.islam@nhcs.com.sg., Liew R; Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857, Singapore. reginald.liew@duke-nus.edu.sg., Shim W; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. winston.shim.s.n@nhcs.com.sg.; Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857, Singapore. winston.shim.s.n@nhcs.com.sg., Cook SA; National Heart Research Institute Singapore, National Heart Centre Singapore, 5th Hospital Drive, Singapore, 169609, Singapore. stuart.cook@duke-nus.edu.sg.; Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, 169857, Singapore. stuart.cook@duke-nus.edu.sg.; National Heart and Lung Institute, Imperial College, South Kensington Campus, London, SW7 2AZ, UK. stuart.cook@duke-nus.edu.sg.
Jazyk: angličtina
Zdroj: Stem cell research & therapy [Stem Cell Res Ther] 2015 Mar 19; Vol. 6, pp. 39. Date of Electronic Publication: 2015 Mar 19.
DOI: 10.1186/s13287-015-0027-z
Abstrakt: 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±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.
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.
Databáze: MEDLINE
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