Techie advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. harbor mutations in the gene, which encodes the K+ channel Kv7.1 mediating the repolarizing current Zotarolimus gene, such as R190Q [84, 85], G269S Zotarolimus and G345E [85, 86], P631fs/33 [87], and a novel heterozygous exon 7 deletion (ex7Del) [88]. In 2010 2010, Moretti and colleagues used Zotarolimus retroviral vectors to generate patient-specific hiPSCs from members of a family affected by the autosomal-dominant missense mutation R190Q in the gene and differentiated the patient-derived cells into functional cardiomyocytes that recapitulated in vitro electrophysiological features of the LQT1 disease phenotype and the therapeutic approach of -blockade [84]. In the same study, hiPSC-CMs helped demonstration of a dominant unfavorable trafficking defect of the mutated channel. Similarly, Egashira et al. identified the same molecular mechanism as being responsible of an LQT1 phenotype in P631fs/33-KCNQ1 mutated hiPSC-CMs [87]. In another study, Liang and colleagues generated a library of hiPSC-CMs from healthy individuals and patients with different hereditary cardiac disorders, including LQT1, for recapitulating and predicting drug-induced arrhythmia. Interestingly, these cells displayed a broad spectrum of cardiotoxicity effects suggesting that disease-specific hiPSC-CMs may accurately predict adverse drug-induced cardiotoxicity [86]. Furthermore, in 2014, Wang et al. generated hiPSCs by overexpressing ion channel genes with dominant negative mutations causing LQT1 (G269S, G345E, and R190Q). To achieve stable transgene expression, these genes were integrated into the AAVS1 safe harbor locus using the Zinc Finger Nuclease technology. Next, transgene cells and isogenic unedited controls were differentiated into cardiomyocytes and recapitulated the LQT1 disease phenotype showing a prolongation in the AP duration (APD) [85]. LQT2 patients carry mutations within the gene, also termed individual ether-a-go-go related gene (mutations continues to be produced and characterized: G1681A [90, 91], A614V [85, 92], R176W [93], N996I [94], A561V [95], A422T [96], and A561P [97]. By executing multi-electrode array, patch-clamp electrophysiology, and medication tests, Matsa et al. confirmed that hiPSC-CMs from two sufferers holding the G1681A mutation demonstrated extended APs but shown different drug-induced awareness [90, 91]. Two indie laboratories applied equivalent approaches for modeling LQT2 by producing hiPSCs from sufferers holding the missense A614V [92] and R176W [93] mutations in the hERG route. However, regardless of the novelty of using individual hiPSC-CMs for modeling LQT2, these research had been performed under non-defined circumstances and genetically, therefore, genetic history variations weren’t considered. To handle this restriction, we modeled LQT2 symptoms by producing hiPSCs from an individual carrying the N996I hERG missense mutation and corrected the mutation by homologous recombination. Next, we introduced the same mutation in hESCs, generating two genetically distinct isogenic pairs of LQTS and control lines [94]. This approach allowed the electrophysiological changes to be attributed to the specific mutation. In another study, hiPSCs were derived using a virus-free method from patients with the A561V missense mutation in the gene and they differentiated Rabbit polyclonal to PIK3CB them into beating cardiomyocytes. Notably, this study provided an approach to rescue the diseased LQT2 phenotype correcting hERG trafficking defects with the pharmacological agent ALLN, demonstrating with patient-specific hiPSC-CMs that re-trafficking of the mutated channels might represent an alternative approach for some mutations [95]. Recently, the use of hiPSC-CMs for modeling LQT2 helped revealing a key role for the transcription factor TBX20 in the regulation of expression [98]. In this study, Caballero and colleagues investigated the electrophysiological effects of the R311C-TBX20 mutation, which is found in individuals affected by LQTS, in hiPSC-CMs. The authors showed that this R311C mutation specifically disables the posttranscriptional activity of TBX20 over LQT3 patients usually carry gain-of-function mutations in the gene, which encodes the Na+ channel NaV1.5 mediating the fast depolarizing current polymorphism. In a similar manner, Fatima et al. reported the generation of hiPSCs from two LQT3 patients carrying two distinct mutations in SCN5A (V240M and R535Q), which resulted in defective biophysical properties of Nav1.5 [102]. Furthermore, in a large family affected by congenital LQT3 syndrome, 15 out of the 23 available individuals were identified as heterozygous carriers of the missense mutation R1644H in (gene, which encodes the Ca2+ channel CaV1.2, the main L-type Ca2+ route within the mammalian center in charge of the plateau stage from the AP and needed for ECC [106]. Yazawa and co-workers modeled the cardiac phenotype of TS including abnormal contraction and successfully.