Functional effects of a missense mutation in HERG associated with type 2 long QT syndrome

Amorós, Irene; Jiménez‐Jáimez, Juan; Tercedor, Luís; Barana, Adriana; Gómez, Ricardo; Fuente, Marta González de la; Dolz-Gaitón, Pablo; Álvarez, Miguel; Martínez-Espín, Esther; Lorente, José A.; Melgares, Rafael; Tamargo, Juan; Delpón, Eva; Caballero, Ricardo

doi:10.1016/j.hrthm.2010.11.032

Cited by 9 publications

(3 citation statements)

References 22 publications

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“…We used a previously validated in silico model of the human ventricular action potential (AP) (11) to test for the effects of the heterozygous p.T152HfsX180 hERG mutation. The model was run for endocardial and epicardial cells at different frequencies ranging between 0.1 and 3 Hz.…”

Section: Resultsmentioning

confidence: 99%

Tbx20 controls the expression of the KCNH2 gene and of hERG channels

Caballero

Utrilla

Amorós

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Long QT syndrome (LQTS) exhibits great phenotype variability among family members carrying the same mutation, which can be partially attributed to genetic factors. We functionally analyzed the KCNH2 (encoding for Kv11.1 or hERG channels) and TBX20 (encoding for the transcription factor Tbx20) variants found by next-generation sequencing in two siblings with LQTS in a Spanish family of African ancestry. Affected relatives harbor a heterozygous mutation in KCNH2 that encodes for p.T152HfsX180 Kv11.1 (hERG). This peptide, by itself, failed to generate any current when transfected into Chinese hamster ovary (CHO) cells but, surprisingly, exerted "chaperone-like" effects over native hERG channels in both CHO cells and mouse atrial-derived HL-1 cells. Therefore, heterozygous transfection of native (WT) and p.T152HfsX180 hERG channels generated a current that was indistinguishable from that generated by WT channels alone. Some affected relatives also harbor the p.R311C mutation in Tbx20. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Tbx20 enhanced human KCNH2 gene expression and hERG currents (I hERG ) and shortened action-potential duration (APD). However, Tbx20 did not modify the expression or activity of any other channel involved in ventricular repolarization. Conversely, p.R311C Tbx20 did not increase KCNH2 expression in hiPSC-CMs, which led to decreased I hERG and increased APD. Our results suggest that Tbx20 controls the expression of hERG channels responsible for the rapid component of the delayed rectifier current. On the contrary, p.R311C Tbx20 specifically disables the Tbx20 protranscriptional activity over KCNH2. Therefore, TBX20 can be considered a KCNH2-modifying gene.is characterized by abnormal prolongation of the QT interval of the electrocardiogram (ECG) and is due to delayed ventricular repolarization. LQTS increases the occurrence of ventricular tachyarrhythmias, particularly torsade de pointes, leading to recurrent syncope, seizures, ventricular fibrillation, and sudden cardiac death (SCD) (1). At least 15 genes have been reported in autosomal-dominant forms of LQTS (1). However, mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) represent the most frequent forms of LQTS (∼90%) (1, 2).KCNH2 encodes Kv11.1, or hERG, channels, which generate the rapid component of the delayed rectifier current (I Kr ) responsible for ventricular repolarization in humans (3). In a Spanish family of African ancestry suffering LQTS, we identified a frameshift and a missense mutation in KCNH2 that were assumed to be the diseasecausing mutations. However, in some family members, we also identified a missense mutation in TBX20 coding for the transcription factor Tbx20, which is necessary in early stages of heart development (4). Importantly, results in flies and mice demonstrated that Tbx20 is also required for maintaining adult heart function (5, 6).Here we have tested the KCNH2 and TBX20 mutations to establish whether they can account for prolongation of repolarization. Our results dem...

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Section: Resultsmentioning

confidence: 99%

Tbx20 controls the expression of the KCNH2 gene and of hERG channels

Caballero

Utrilla

Amorós

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Written informed consent was obtained for the genetic screening test of the proband and all the relatives studied. Genomic DNA was isolated from white blood cells by conventional methods [14,15]. The whole codifying sequence and the flanking intronic regions of KCNQ1 , KCNH2 , KCNJ2, SCN5A , KCNE1 , and KCNE2 genes were amplified by polymerase chain reaction and directly sequenced.…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of a Novel Frameshift Mutation in the C-terminus of the Nav1.5 Channel Underlying a Brugada Syndrome with Variable Expression in a Spanish Family

Dolz-Gaitón

Núñez

et al. 2013

PLoS ONE

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IntroductionWe functionally analyzed a frameshift mutation in the SCN5A gene encoding cardiac Na+ channels (Nav1.5) found in a proband with repeated episodes of ventricular fibrillation who presented bradycardia and paroxysmal atrial fibrillation. Seven relatives also carry the mutation and showed a Brugada syndrome with an incomplete and variable expression. The mutation (p.D1816VfsX7) resulted in a severe truncation (201 residues) of the Nav1.5 C-terminus. Methods and ResultsWild-type (WT) and mutated Nav1.5 channels together with hNavβ1 were expressed in CHO cells and currents were recorded at room temperature using the whole-cell patch-clamp. Expression of p.D1816VfsX7 alone resulted in a marked reduction (≈90%) in peak Na+ current density compared with WT channels. Peak current density generated by p.D1816VfsX7+WT was ≈50% of that generated by WT channels. p.D1816VfsX7 positively shifted activation and inactivation curves, leading to a significant reduction of the window current. The mutation accelerated current activation and reactivation kinetics and increased the fraction of channels developing slow inactivation with prolonged depolarizations. However, late INa was not modified by the mutation. p.D1816VfsX7 produced a marked reduction of channel trafficking toward the membrane that was not restored by decreasing incubation temperature during cell culture or by incubation with 300 μM mexiletine and 5 mM 4-phenylbutirate. ConclusionDespite a severe truncation of the C-terminus, the resulting mutated channels generate currents, albeit with reduced amplitude and altered biophysical properties, confirming the key role of the C-terminal domain in the expression and function of the cardiac Na+ channel.

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“…Of the plasma membrane ion channels that contribute to myocardial repolarization reserve, the rapidly rectifying inward potassium current, I Kr , has been most widely recognized to be responsible for TdP risk (10–17). In contrast, the slow delayed rectifier potassium current (I Ks ) contribution to TdP formation has been more controversial (18), as the effects of selective I Ks -blocking drugs on action potential duration (APD) have been variable (19–22).…”

Section: Relating Risk Factors To Pharmacologic Mechanismsmentioning

confidence: 99%

Proarrhythmic and Torsadogenic Effects of Potassium Channel Blockers in Patients

McCauley

Vallabhajosyula

Darbar

2016

Cardiac Electrophysiology Clinics

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Summary The most common arrhythmia requiring drug therapy is atrial fibrillation, which affects 2–5 million Americans and continues to be a major cause of morbidity and increased mortality. Despite recent advances in catheter-based and surgical therapies, antiarrhythmic drugs continue to be the mainstay of therapy for most patients with symptomatic AF. However, many antiarrhythmics block the rapid component of the cardiac delayed rectifier potassium current (IKr) as a major mechanism of action, and marked QT prolongation and pause-dependent polymorphic ventricular tachycardia (torsades de pointes) are major class toxicities. Although this arrhythmia is usually seen in patients with one of the congenital long QT syndromes, torsades de pointes has also been observed with certain antibiotics, antipsychotics, antihistamines and chemotherapeutic agents and is a leading cause of post-market drug withdrawal and relabeling. Clinical risk factors associated with drug-induced long QT syndrome include female gender, bradycardia, electrolyte disturbances, recent conversion from atrial fibrillation to sinus rhythm, variations in drug distribution and sub-clinical long QT syndrome. A unifying concept of reduced repolarization reserve has been proposed to explain the variable risk of torsades de pointes. In this monograph, we provide a historical perspective on drug-induced long QT syndrome, briefly discuss the underlying mechanisms, and detail recent advances in torsadogenic risk factors and the complex interplay between individual patient-related clinical risk characteristics and the development of torsades de pointes with potassium-channel blocking drugs.

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Functional effects of a missense mutation in HERG associated with type 2 long QT syndrome

Cited by 9 publications

References 22 publications

Tbx20 controls the expression of the KCNH2 gene and of hERG channels

Tbx20 controls the expression of the KCNH2 gene and of hERG channels

Functional Characterization of a Novel Frameshift Mutation in the C-terminus of the Nav1.5 Channel Underlying a Brugada Syndrome with Variable Expression in a Spanish Family

Proarrhythmic and Torsadogenic Effects of Potassium Channel Blockers in Patients

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