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Cell Journal، جلد ۱۶، شماره Suppl ۱، صفحات ۶-۶
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عنوان انگلیسی Is-5: Human Pluripotent Stem Cells for Modelling and Correcting Long-QT Syndrome
چکیده انگلیسی مقاله Objective: Long-QT syndrome (LQTS) is an electrical disease of the heart characterized by delayed cardiac repolarization, which causes prolongation of the QT interval (the distance between the Q and T peaks) on the surface electrocardiogram. Its clinical manifestations are often dramatic, with ventricular tachycardia and syncope resulting in cardiac arrest and sudden death. The LQTS variants LQT1, LQT2, and LQT3 comprise the majority documented to date. The objectives of our studies were 1) to demonstrate that human induced pluripotent stem cells (hiPSCs) are a suitable tool to recapitulate the LQT1 phenotype by studying the R190QKCNQ1 mutation; 2) to investigate whether elevation of the intact repolarising current IKr could effectively restore normal QT duration if KCNQ1 is mutated; 3) to study the LQT2-associated N996I-KCNH2 mutation under genetically defined conditions, by generating two genetically distinct isogenic pairs of LQT and control lines. Materials and Methods: We reprogrammed skin fibroblasts from patients affected by LQT1 and LQT2 syndrome and healthy controls. The generated hiPSCs were differentiated into cardiomyocytes (CMs) and their electrophysiological properties were studied with the patch-clamp technique. Gene targeting based on homologous recombination was used to correct LQT2 hiPSCs and introduce the same KCNH2 mutation in human embryonic stem cells (hESCs). Results: We generated patient-specific hiPSCs from members of a family affected by LQT1 and differentiated into functional CMs. These cells recapitulated the electrophysiological features of the disorder, including prolongation of the action potential duration (APD), as compared with cells from healthy controls. Further characterization of the role of the R190Q-KCNQ1 mutation in the disease pathogenesis revealed a dominant negative trafficking defect associated with a 70% to 80% reduction in the KCNQ1-conducted IKs current and altered channel activation and deactivation properties. Furthermore, mutated CMs had an increased susceptibility to catecholamine-induced tachyarrhythmia and beta-blockade attenuated this phenotype. Next, a unique specific chemical activator for IKr that reduced voltage sensitivity of inactivation, caused a dose-dependent shortening of the APD and was able to normalize action potentials of CMs of patients with LQT1. Finally, we derived hiPSCs from a patient carrying the LQT2-associated N996I-KCNH2 mutation and corrected it. Furthermore, we introduced the same mutation in hESCs, generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the IKr current conducted by the KCNH2 channel and the APD in hiPSC-derived CMs. Introduction of the same mutation reduced IKr and prolonged the APD in hESC-derived CMs. Further characterization of N996I-KCNH2 pathogenesis revealed a trafficking defect. Conclusion: Our results demonstrate that hiPSC models recapitulate aspects of genetic cardiac diseases, including APD prolongation, altered IKs, and an abnormal response to catecholamine stimulation, with a protective effect of beta-blockade. Furthermore our studies provide both the theoretical basis and experimental support for compensatory normalization of APD by a pharmacological agent. Finally we have demonstrated that the N996I-KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/299
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