Compound heterozygosity for mutations Asp611→Tyr in KCNQ1 and Asp609→Gly in KCNH2 associated with severe long QT syndrome

2005 ◽  
Vol 108 (2) ◽  
pp. 143-150 ◽  
Author(s):  
Masato YAMAGUCHI ◽  
Masami SHIMIZU ◽  
Hidekazu INO ◽  
Hidenobu TERAI ◽  
Kenshi HAYASHI ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Clinical Manifestations ◽  
Torsades De Pointes ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Wild Type ◽  
Long Qt ◽  
Mild Phenotype ◽  
Electrophysiological Properties ◽  
Qt Syndrome

LQTS (long QT syndrome) is an inherited cardiac disorder characterized by prolongation of QT interval, torsades de pointes and sudden death. We have identified two heterozygous missense mutations in the KCNQ1 and KCNH2 (also known as HERG) genes [Asp611→Tyr (D611Y) in KCNQ1 and Asp609→Gly (D609G) in KCNH2] in a 2-year-old boy with LQTS. The aim of the present study was to characterize the contributions of the mutations in the KCNQ1 and KCNH2 genes relative to the clinical manifestations and electrophysiological properties of LQTS. Six of 11 carriers of D611Y in KCNQ1 had long QT intervals. D609G in KCNH2 was detected only in the proband. Studies on the electrophysiological alterations due to the two missense mutations revealed that the D611Y mutation in KCNQ1 did not show a significant suppression of the currents compared with wild-type, but the time constants of current activation in the mutants were increased compared with that in the wild-type. In contrast, the D609G mutation in KCNH2 showed a dominant-negative suppression. Our results suggest that the mild phenotype produced by the D611Y mutation in KCNQ1 became more serious by addition of the D609G mutation in KCNH2 in the proband.

scholarly journals Multiple splicing defects caused by hERG splice site mutation 2592+1G>A associated with long QT syndrome

2011 ◽  
Vol 300 (1) ◽  
pp. H312-H318 ◽  
Author(s):  
Matthew R. Stump ◽  
Qiuming Gong ◽  
Zhengfeng Zhou
Keyword(s):  
Splice Site ◽  
Long Qt Syndrome ◽  
Splice Site Mutation ◽  
Dominant Negative ◽  
Wild Type ◽  
Site Mutation ◽  
Long Qt ◽  
Herg Current ◽  
Qt Syndrome ◽  
Splicing Defects

Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene ( hERG). Cryptic splice site activation in hERG has recently been identified as a novel pathogenic mechanism of LQT2. In this report, we characterize a hERG splice site mutation, 2592+1G>A, which occurs at the 5′ splice site of intron 10. Reverse transcription-PCR analyses using hERG minigenes transfected into human embryonic kidney-293 cells and HL-1 cardiomyocytes revealed that the 2592+1G>A mutation disrupted normal splicing and caused multiple splicing defects: the activation of cryptic splice sites within exon 10 and intron 10 and complete intron 10 retention. We performed functional and biochemical analyses of the major splice product, hERGΔ24, in which 24 amino acids within the cyclic nucleotide binding domain of the hERG channel COOH-terminus is deleted. Patch-clamp experiments revealed that the splice mutant did not generate hERG current. Western blot and immunostaining studies showed that mutant channels did not traffic to the cell surface. Coexpression of wild-type hERG and hERGΔ24 resulted in significant dominant-negative suppression of hERG current via the intracellular retention of the wild-type channels. Our results demonstrate that 2592+1G>A causes multiple splicing defects, consistent with the pathogenic mechanisms of long QT syndrome.

A rare indication of permanent pacemaker implantation in children: congenital long QT syndrome

2020 ◽  
Vol 30 (12) ◽  
pp. 1880-1881
Author(s):  
Mehmet Taşar ◽  
Nur Dikmen Yaman ◽  
Huseyin Dursin ◽  
Murat Şimşek ◽  
Senem Özgür
Keyword(s):  
Sudden Death ◽  
Long Qt Syndrome ◽  
Pacemaker Implantation ◽  
Torsades De Pointes ◽  
Permanent Pacemaker ◽  
Long Qt ◽  
Permanent Pacemaker Implantation ◽  
Qt Syndrome ◽  
Congenital Lqts ◽  
Congenital Long Qt Syndrome

AbstractCongenital Long QT Syndrome (LQTS) is a dangerous arrhythmic disorder that can be diagnosed in children with bradycardia. It is characterised by a prolonged QT interval and torsades de pointes that may cause sudden death. Long QT syndrome is an ion channelopathy with complex molecular and physiological infrastructure. Unlike the acquired type, congenital LQTS has a genetic inheritance and it may be diagnosed by syncope, stress in activity, cardiac dysfunction, sudden death or sometimes incidentally. Permanent pacemaker implantation is required for LQTS with resistant bradycardia even in children to resolve symptoms and avoid sudden death.

scholarly journals Peripartum Cardiomyopathy Presenting with Syncope due to Torsades de Pointes: a Case of Long QT Syndrome with a Novel KCNH2 Mutation

2012 ◽  
Vol 51 (5) ◽  
pp. 461-464 ◽  
Author(s):  
Orie Nishimoto ◽  
Morihiro Matsuda ◽  
Kei Nakamoto ◽  
Hirohiko Nishiyama ◽  
Kazuya Kuraoka ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Torsades De Pointes ◽  
Peripartum Cardiomyopathy ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Dobutamine Infusion for Unmasking Long QT Syndrome and Torsades de Pointes

2009 ◽  
Vol 32 (6) ◽  
pp. E78-E81 ◽  
Author(s):  
Fang Quan ◽  
Gao Peng ◽  
Cheng Kangan ◽  
Hu Dayi ◽  
Li Cuilan ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Torsades De Pointes ◽  
Dobutamine Infusion ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Prolonged QTc: "Mind the Gap"

2014 ◽  
Vol 2 (1) ◽  
pp. 44-45
Author(s):  
Ahmad Mursel Anam ◽  
Raihan Rabbani ◽  
Farzana Shumy ◽  
M Mufizul Islam Polash ◽  
M Motiul Islam ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Long Qt Syndrome ◽  
Qt Interval ◽  
Torsades De Pointes ◽  
Junior Doctors ◽  
Long Qt ◽  
Acquired Long Qt Syndrome ◽  
Prolonged Qt Interval ◽  
Prolonged Qt ◽  
Qt Syndrome

We report a case of drug induced torsades de pointes, following acquired long QT syndrome. The patient got admitted for shock with acute abdomen. The initial prolonged QT-interval was missed, and a torsadogenic drug was introduced post-operatively. Patient developed torsades de pointes followed by cardiac arrest. She was managed well and discharged without complications. The clinical manifestations of long QT syndromes, syncope or cardiac arrest, result from torsades de pointes. As syncope or cardiac arrest have more common differential diagnoses, even the symptomatic long QT syndrome are commonly missed or misdiagnosed. In acquired long QT syndrome with no prior suggestive feature, it is not impossible to miss the prolonged QT-interval on the ECG tracing. We share our experience so that the clinicians, especially the junior doctors, will be more alert on checking the QT-interval even in asymptomatic patients. DOI: http://dx.doi.org/10.3329/bccj.v2i1.19970 Bangladesh Crit Care J March 2014; 2 (1): 44-45

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

2011 ◽  
Vol 301 (1) ◽  
pp. C75-C85 ◽  
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.

Pauses after burst pacing provoke afterdepolarizations and torsades de pointes in a patient with long QT syndrome

Heart Rhythm ◽  
2004 ◽  
Vol 1 (6) ◽  
pp. 720-723 ◽  
Author(s):  
Paulus Kirchhof ◽  
Stephan Zellerhoff ◽  
Gerold Mönnig ◽  
Eric Schulze-Bahr
Keyword(s):  
Long Qt Syndrome ◽  
Torsades De Pointes ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Delayed diagnosis of long QT syndrome in a patient with seizures

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.

A Candidate Locus Approach Identifies a Long QT Syndrome Gene Mutation

2003 ◽  
Vol 5 (2) ◽  
pp. 97-104 ◽  
Author(s):  
Theresa A. Beery ◽  
Macaira Dyment ◽  
Kerry Shooner ◽  
Timothy K. Knilans ◽  
D. Woodrow Benson
Keyword(s):  
Potassium Channel ◽  
Long Qt Syndrome ◽  
Family Members ◽  
Torsades De Pointes ◽  
Sudden Onset ◽  
Coding Region ◽  
Long Qt ◽  
Candidate Locus ◽  
Qt Intervals ◽  
Qt Syndrome

Long QT syndrome is an inherited disorder that results in lengthened cardiac repolarization. It can lead to sudden onset of torsades de pointes, ventricular fibrillation, and death. The authors obtained a family history, performed electrocardiograms, and drew blood for DNA extraction and genotyping from 15 family members representing 4 generations of an affected family. Seven individuals demonstrated prolonged QT intervals. The authors used polymorphic short tandem repeat markers at known LQTS loci, which indicated linkage to chromosome 11p15.5 where the potassium channel, KCNQ1, is encoded. Polymerase chain reaction was used to amplify the coding region of KCNQ1. During survey of the KCNQ1 coding region, a G-to-A transition (G502A) was identified. DNA from all clinically affected but from none of the clinically unaffected family members carried the G-to-A transition. The candidate locus approach allowed an efficient mechanism to uncover the potassium channel mutation causing LQTS in this family.

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