R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome

Mesquita, Fernanda; Arantes, Paulo C.; Kasai-Brunswick, Taís Hanae; Araujo, Dayana S.; Gubert, Fernanda; Monnerat, Gustavo; Santos, Dos; Neiman, Gabriel; Leitão, Isabela C.; Barbosa, Raiana Andrade Quintanilha; Coutinho, Jorge Luiz Albuquerque; Vaz, Isadora May; Santos, Marcus N. dos; Borgonovo, Tamara; Cruz, Fernando E.S.; Miriuka, Santiago Gabriel; Medei, Emiliano; Carvalho, Antônio Carlos Campos de; Carvalho, Adriana Bastos

doi:10.1038/s41598-019-55837-w

Cited by 25 publications

(20 citation statements)

References 41 publications

(39 reference statements)

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“…However, HiPSC-derived myocytes from patients with defined mutations using VARRÓ ET AL. 1116 Physiol Rev VOL 101 JULY 2021 www.prv.org CRISPR/Cas9-edited cells can mimic diseases (688,(695)(696)(697)(698) that are often hard or impossible to recreate properly in animal experiments. Recent efforts to culture and continuously pace HiPSC-derived cardiomyocytes cultured in collagen gels as "engineered heart tissue" represent a new two-dimensional (2-D) and threedimensional (3-D) approach (699-701), since it resembles more the mature myocardium.…”

Section: Species-dependent Differences In Action Potentialsmentioning

confidence: 99%

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

Varró

Tomek

Nagy

et al. 2021

Physiological Reviews

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Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells, and their underlying ionic mechanisms. It is therefore critical to further unravel the patho-physiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodelling) are discussed. The focus is human relevant findings obtained with clinical, experimental and computational studies, given that interspecies differences make the extrapolation from animal experiments to the human clinical settings difficult. Deepening the understanding of the diverse patholophysiology of human cellular electrophysiology will help developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.

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Section: Species-dependent Differences In Action Potentialsmentioning

confidence: 99%

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

Varró

Tomek

Nagy

et al. 2021

Physiological Reviews

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“… 205 Overall, hiPSC-CMs have been widely used for LQTS modeling and also as a powerful tool for understanding LQTS disease molecular and cellular mechanisms, as well as to determine in a patient-specific manner drug treatment screening. 206 , 207 , 208 , 209 , 210 , 211 , 212 The use of this hiPSC-CM model has really allowed for major advancement in the study of LQTS in the last few years and will continue to be the ideal platform to study these cardiac genetic diseases, as they allow for the use of cells containing the whole genetic background of the patients.…”

Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.

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“…Expression of pluripotency markers was determined by RT-PCR and flow cytometry (BD Accuri C6, BD FACSAria II and FlowJo software version 1). The reprogramming method used has already been validated ( Kasai-Brunswick et al, 2018 ; Mesquita et al, 2019 ; Gubert et al, 2019a ; Gubert et al ., 2019b ).…”

Section: Methodsmentioning

confidence: 99%

Chromosomal aberrations after induced pluripotent stem cells reprogramming

et al. 2021

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Induced pluripotent stem cells (iPSCs) are generated from adult cells that have been reprogrammed to pluripotency. However, in vitro cultivation and genetic reprogramming increase genetic instability, which could result in chromosomal abnormalities. Maintenance of genetic stability after reprogramming is required for possible experimental and clinical applications. The aim of this study was to analyze chromosomal alterations by using the G-banding karyotyping method applied to 97 samples from 38 iPSC cell lines generated from peripheral blood or Wharton’s jelly. Samples from patients with long QT syndrome, Jervell and Lange-Nielsen syndrome and amyotrophic lateral sclerosis and from normal individuals revealed the following chromosomal alterations: acentric fragments, chromosomal fusions, premature centromere divisions, double minutes, radial figures, ring chromosomes, polyploidies, inversions and trisomies. An analysis of two samples generated from Wharton’s jelly before and after reprogramming showed that abnormal clones can emerge or be selected and generate an altered lineage. IPSC lines may show clonal and nonclonal chromosomal aberrations in several passages (from P6 to P34), but these aberrations are more common in later passages. Many important chromosomal aberrations were detected, showing that G-banding is very useful for evaluating genetic instability with important repercussions for the application of iPSC lines.

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R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome

Cited by 25 publications

References 41 publications

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

Long QT syndrome – Bench to bedside

Chromosomal aberrations after induced pluripotent stem cells reprogramming

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