Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome

KCNQ1 is a gene encoding an α subunit of voltage-gated cardiac K+ channels, with properties similar to the slowly activating delayed rectifier K+ current, and one of the genes causing long QT syndrome (LQTS). However, genotype–phenotype correlations of the KCNQ1 gene mutations are not fully understood. The aims of this study were to identify a mutation in the KCNQ1 gene in patients with LQTS, and to characterize the clinical manifestations and electrophysiological properties of the mutation. We screened and identified mutations by PCR, single-strand conformational polymorphism analysis and DNA sequencing. We identified a novel mutation [Phe193Leu (F193L)] in the KCNQ1 gene in one family with LQTS. The patients with this mutation showed a mildly affected phenotype. The proband was a 17-year-old girl who had a prolonged QT interval. Her elder brother, father and paternal grandmother also had the mutation. None of them had any history of syncope. Sudden death was not found in this family. Next, we studied the electrophysiological characteristics of the F193L mutation in the KCNQ1 gene using the expression system in Xenopus oocytes and the two-microelectrode voltage-clamp technique. Co-expression of F193L KCNQ1 with the K+ channel minK suppressed peak (by 23.3%) and tail (by 38.2%) currents compared with those obtained by the combination of wild-type (WT) KCNQ1 and minK. Time constants of current activation in F193L KCNQ1 and F193L KCNQ1+minK were significantly slower than those of WT KCNQ1 and WT KCNQ1+minK. This electrophysiological study indicates that F193L causes less severe KCNQ1 current suppression, and thereby this mutation may result in a mildly affected phenotype.

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Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome

Clinical Science ◽

10.1042/cs20020152 ◽

2003 ◽

Vol 104 (4) ◽

pp. 377 ◽

Cited By ~ 1

Author(s):

Masato YAMAGUCHI ◽

Masami SHIMIZU ◽

Hidekazu INO ◽

Hidenobu TERAI ◽

Kenshi HAYASHI ◽

...

Keyword(s):

Long Qt Syndrome ◽

Novel Mutation ◽

Long Qt ◽

Kcnq1 Gene ◽

Qt Syndrome ◽

Electrophysiological Characterization

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Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome

Circulation ◽

10.1161/circulationaha.120.051836 ◽

2021 ◽

Author(s):

Steven M. Dotzler ◽

C.S. John Kim ◽

William A.C. Gendron ◽

Wei Zhou ◽

Dan Ye ◽

...

Keyword(s):

Gene Therapy ◽

Long Qt Syndrome ◽

Delayed Rectifier ◽

Loss Of Function ◽

Wild Type ◽

Long Qt ◽

Α Subunit ◽

Cardiac Model ◽

Qt Syndrome

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit which is essential for cardiac repolarization, providing the slow delayed rectifier current (IKs). No current therapies target the molecular cause of LQT1. Methods: A dual-component "suppression-and-replacement" (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 shRNA and a "shRNA-immune" (shIMM) KCNQ1 cDNA modified with silent variants in the shRNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated via heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from four patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for two LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and three LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of KCNQ1-shIMM as measured by allele-specific qRT-PCR and western blot. Using FluoVolt voltage dye to measure the cardiac APD in the four LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% (APD 90 ) and 50% (APD 50 ) repolarization resulting in APD values similar to those of the two isogenic controls. Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of LQTS. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, co-transfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression-and-replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.

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hERG channel trafficking: novel targets in drug-induced long QT syndrome

Biochemical Society Transactions ◽

10.1042/bst0351060 ◽

2007 ◽

Vol 35 (5) ◽

pp. 1060-1063 ◽

Cited By ~ 93

Author(s):

A. Dennis ◽

L. Wang ◽

X. Wan ◽

E. Ficker

Keyword(s):

Long Qt Syndrome ◽

Heat Shock Protein 90 ◽

Delayed Rectifier ◽

Cardiac Events ◽

Long Qt ◽

Drug Induced ◽

Α Subunit ◽

Human Cardiomyocytes ◽

Qt Syndrome ◽

Therapeutic Compounds

The cardiac potassium channel hERG (human ether-a-go-go-related gene) encodes the α-subunit of the rapid delayed rectifier current IKr in the heart, which contributes to terminal repolarization in human cardiomyocytes. Direct block of hERG/IKr channels by a large number of therapeutic compounds produces acLQTS [acquired LQTS (long QT syndrome)] characterized by drug-induced QT prolongation and torsades de pointes arrhythmias. The cardiotoxicity associated with unintended hERG block has prompted pharmaceutical companies to screen developmental compounds for hERG blockade and made hERG a major target in drug safety programmes. More recently, a novel form of acLQTS has been discovered that may go undetected in most conventional safety assays. Several therapeutic compounds have been identified that reduce hERG/IKr currents not by direct block but by inhibition of hERG/IKr trafficking to the cell surface. Important examples are antineoplastic Hsp90 (heat-shock protein 90) inhibitors such as (i) geldanamycin, (ii) the leukaemia drug arsenic trioxide, (iii) the antiprotozoical pentamidine, (iv) probucol, a cholesterol-lowering drug, and (v) fluoxetine, a widely used antidepressant. Increased awareness of drug-induced hERG trafficking defects will help to further reduce the potentially lethal adverse cardiac events associated with acLQTS.

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A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome

Heart Rhythm ◽

10.1016/j.hrthm.2012.09.053 ◽

2013 ◽

Vol 10 (1) ◽

pp. 61-67 ◽

Cited By ~ 14

Author(s):

Li Liu ◽

Kenshi Hayashi ◽

Tomoya Kaneda ◽

Hidekazu Ino ◽

Noboru Fujino ◽

...

Keyword(s):

Long Qt Syndrome ◽

Novel Mutation ◽

Clinical Manifestations ◽

Long Qt ◽

Qt Syndrome

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Trafficking-deficient hERG K+ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER

AJP Cell Physiology ◽

10.1152/ajpcell.00494.2010 ◽

2011 ◽

Vol 301 (1) ◽

pp. C75-C85 ◽

Cited By ~ 24

Author(s):

Jennifer L. Smith ◽

Christie M. McBride ◽

Parvathi S. Nataraj ◽

Daniel C. Bartos ◽

Craig T. January ◽

...

Keyword(s):

Golgi Apparatus ◽

Long Qt Syndrome ◽

Functional Expression ◽

Delayed Rectifier ◽

Temperature Sensitive ◽

Missense Mutations ◽

Long Qt ◽

Delayed Rectifier Current ◽

Golgi Compartment ◽

Qt Syndrome

The human ether-a-go-go related gene ( hERG) encodes the voltage-gated K+ channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.

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Delayed diagnosis of long QT syndrome in a patient with seizures

Hong Kong Journal of Emergency Medicine ◽

10.1177/1024907918754921 ◽

2019 ◽

Vol 26 (3) ◽

pp. 190-193

Author(s):

Seung Yong Shin ◽

Jun Young Hong ◽

Dong Hoon Lee

Keyword(s):

Emergency Department ◽

Long Qt Syndrome ◽

Delayed Diagnosis ◽

Clinical Manifestations ◽

Initial Assessment ◽

Long Qt ◽

Prolonged Qt Interval ◽

Qt Syndrome ◽

Seizure Episode ◽

Diagnostic Work

Introduction: Long QT syndrome accompanied by a seizure episode is often misdiagnosed as primary epilepsy. Although patients with Long QT syndrome who are misdiagnosed and improperly managed are likely to result in fatality, their first clinical manifestations are seizure episodes in many cases. Case presentation: A 17-year-old boy visited the emergency department with poorly controlled seizure during epilepsy treatment was found to have been misdiagnosed with epilepsy when he was 7 years old. His electrocardiography showed a prolonged QT interval. After careful re-evaluation, he was finally diagnosed with Long QT syndrome and recovered without any seizure episodes in the absence of anti-epileptic agents. Discussion and conclusion: Careful initial assessment including repetitive electrocardiography, when abnormal, is required for those who visit the emergency department with a seizure or who show no definite abnormalities in diagnostic work up process.

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Balance Between Rapid Delayed Rectifier K + Current and Late Na + Current on Ventricular Repolarization

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.119.008130 ◽

2020 ◽

Vol 13 (4) ◽

Author(s):

Bence Hegyi ◽

Ye Chen-Izu ◽

Leighton T. Izu ◽

Sridharan Rajamani ◽

Luiz Belardinelli ◽

...

Keyword(s):

Heart Failure ◽

Long Qt Syndrome ◽

Therapeutic Potential ◽

Heart Diseases ◽

Ionic Currents ◽

Close Correlation ◽

Delayed Rectifier ◽

Long Qt ◽

Comparable Amount ◽

Qt Syndrome

Background: Rapid delayed rectifier K + current (I Kr ) and late Na + current (I NaL ) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. Methods: Physiological self AP-clamp was used to measure I NaL and I Kr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between I Kr and I NaL affects repolarization stability in health and disease conditions. Results: We found comparable amount of net charge carried by I Kr and I NaL during the physiological AP, suggesting that outward K + current via I Kr and inward Na + current via I NaL are in balance during physiological repolarization. Remarkably, I Kr and I NaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block I Kr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na + channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit I NaL sufficiently restored APD to control in both cases. Importantly, I NaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I NaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by I NaL inhibition, increased by I Kr inhibition, and restored by combined I NaL and I Kr inhibitions. Conclusions: Our data demonstrate that I Kr and I NaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

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