Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca2+ currents and promote proarrhythmic behavior in ventricular myocytes

Limpitikul, Worawan B.; Dick, Ivy E.; Joshi-Mukherjee, Rosy; Overgaard, Michael Toft; George, Alfred L.; Yue, David T.

doi:10.1016/j.yjmcc.2014.04.022

Cited by 155 publications

(239 citation statements)

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“…18 Furthermore, LQTScausing calmodulin mutations disrupt calcium-dependent inactivation of the LTCC. 25,26 Therefore, it is biologically plausible that a decrease in I Ca,L inactivation, caused by loss of triadin, could lead to prolonged cardiac action potential and an LQTS phenotype.…”

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confidence: 99%

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

et al. 2015

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Background-Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTSsusceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. Methods and Results-We performed whole-exome sequencing child-parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole-exome sequencing and variant filtration, a homozygous p.D18fs*13 TRDN-encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V 1 through V 4 , with either persistent or transient QT prolongation and severe disease expression of exercise-induced cardiac arrest in early childhood (≤3 years of age) and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients ≤10 years of age (5 of 10, 50%) compared with older patients (0 of 24, 0%; P=0.0009). encode for critical ion channel α-subunits responsible for the cardiac action potential. However, ≈20% of patients with clinically definite LQTS remain genetically elusive. Conclusions-We identified

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confidence: 99%

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

et al. 2015

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“…Using FRET-based binding assays, the Yue lab demonstrated that the mutant CaMs had preserved binding with the L-type channel, suggesting that a fraction of L-type channels were occupied by a mutant CaM. Through modeling and further electrophysiology, they showed that the large effect that mutant CaM has on a small fraction of channels was sufficient to produce a significant reduction of CDI, 22 leading to a large prolongation of action potential duration (Fig. 7B, right).…”

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confidence: 99%

“…2) binding to troponin C. 21 Such dependence of cardiac excitationcontraction coupling on Ca 2C illustrates the critical nature of Ca 2C signaling, but it does not represent the full set of pathways dependent on Ca 2C within the heart. Ca 2C entry through L-type channels is also a major factor in setting the action potential duration of the heart, 22 making physiological regulation of these channels a necessity 16 as well as an important substrate for pathology. 22,23 Additionally, Ca 2C activates a number of kinases and phosphatases including CaMKII and calcineurin, both of which may play an important role in cardiac hypertrophy and heart failure.…”

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confidence: 99%

“…Ca 2C entry through L-type channels is also a major factor in setting the action potential duration of the heart, 22 making physiological regulation of these channels a necessity 16 as well as an important substrate for pathology. 22,23 Additionally, Ca 2C activates a number of kinases and phosphatases including CaMKII and calcineurin, both of which may play an important role in cardiac hypertrophy and heart failure. 24,25 Excitation-contraction coupling is not only a vital component of cardiac function, but is a fundamental mechanism of muscle contraction.…”

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A rendezvous with the queen of ion channels: Three decades of ion channel research by David T Yue and his Calcium Signals Laboratory

et al. 2015

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“…8,9 The new work in F142L hiPSC-CMs was also able to exclude other possible causes of LQTS and ventricular arrhythmia. For example, they found that alterations in the slowly activating delayed rectifier current (I Ks ) or the late sodium current (I Na,L ), both of which are regulated by CaM (Figure 1), were not responsible for the prolonged action potentials of F142L hiPSC-CMs.…”

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confidence: 99%

Modelling human calmodulinopathies with induced pluripotent stem cells: progress and challenges

Gómez-Hurtado¹,

Blackwell²,

Knollmann³

2017

Cardiovascular Research

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This editorial refers to 'Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes' by M. Rocchetti et al., Calmodulin (CaM) is a ubiquitous calcium binding protein that regulates a wide range of biological processes. Consistent with its critical importance for basic cellular functions, mammals have three different CaM genes encoding an identical CaM protein. The first human CaM disease mutations were only recently discovered. Surprisingly, they were associated with a range of ventricular arrhythmia syndromes: Catecholaminergic Polymorphic Ventricular Tachycardia, 1-3 early-onset long-QT syndrome (LQTS), 4,5 and idiopathic ventricular fibrillation. 6 The puzzling question of how CaM missense mutations that only affect one out of six alleles can cause such severe and divergent arrhythmia phenotypes had until very recently only been studied using in vitro model systems, with somewhat conflicting results. In the current issue of CVR, Rochetti et al. 7 tried to overcome the limitations of non-human models by studying human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the CALM1-F142L mutation, a mutation that causes a severe loss of Ca 2þ binding to CaM in vitro. 4 hiPSC-CMs were generated from skin fibroblasts of a 14-year-old white male who presented with recurrent episodes of non-sustained ventricular tachycardia, T-wave alternans, prolonged QTc interval, and cardiac arrest resulting from ventricular fibrillation.4 Rochetti et al. 7 reported that the patient-specific F142L hiPSC-CMs had very long action potentials, which mirrored the severe QT prolongation found in the patient. The authors identified a severe impairment in Ca 2þ -dependent inactivation (CDI) of L-type calcium currents (LTCC)as the cause of the action potential prolongation; a mechanism previously predicted from studies of the F142L-CaM in heterologous expression systems and in rodent cardiomyocytes. 8,9 The new work in F142L hiPSC-CMs was also able to exclude other possible causes of LQTS and ventricular arrhythmia. For example, they found that alterations in the slowly activating delayed rectifier current (I Ks ) or the late sodium current (I Na,L ), both of which are regulated by CaM (Figure 1), were not responsible for the prolonged action potentials of F142L hiPSC-CMs. This is an important finding, because mutations resulting in reduced I Ks and or increased I Na,L cause LQTS type 1, 3, and 5; all of which have been successfully modelled using patient-derived hiPSC-CMs. 10 Hence, together with another recent study examining hiPSC-CMs from a patient carrying the CALM1-D130G LQTS mutation, 11 the report by Rochetti et al. establishes the utility of hiPSC-CMs to investigate the pathophysiology of CaM variants identified in LQTS patients. Nevertheless, there are some important limitations to consider. The use of CRISPR/Cas9 to correct the putative mutation and generate isogenic controls is becoming increasingly standard in ...

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Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca2+ currents and promote proarrhythmic behavior in ventricular myocytes

Cited by 155 publications

References 54 publications

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

A rendezvous with the queen of ion channels: Three decades of ion channel research by David T Yue and his Calcium Signals Laboratory

Modelling human calmodulinopathies with induced pluripotent stem cells: progress and challenges

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