A novel mutation in the KCNH2 gene associated with short QT syndrome

Sun, Yaxun; Quan, Xiao‐Qing; Fromme, Samantha; Cox, Robert H.; Zhang, Ping; Zhang, Li; Guo, Dan; Guo, Jihong; Patel, Chinmay; Kowey, Peter R.; Yan, Gan‐Xin

doi:10.1016/j.yjmcc.2010.11.017

Cited by 71 publications

(89 citation statements)

References 28 publications

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“…However, the recent discovery of a clinically occurring pore helix mutation, T618I, that results in a marked alteration of inactivation gating (27) prompted us to re-examine the role of the pore helix in Kv11.1 inactivation, starting with an analysis of the T618I channel. Rates of onset and recovery from inactivation were obtained from families of current traces for WT and T618I mutant channels, as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inherited mutations that enhance (25) or reduce (26,27) inactivation result in delayed or accelerated repolarization of the heart, respectively, and consequently greatly increase the risk of sudden cardiac arrest (26 -28). Kv11.1 channels are also of great interest in terms of understanding selectivity filter gating as the open-to-inactivated state transition can be easily isolated from the much slower closedto-open state gating transition (29, 30), making it amenable to study by REFER analysis (13).…”

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confidence: 99%

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Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

Perry

Vandenberg

2013

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

Perry

Vandenberg

2013

Journal of Biological Chemistry

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“…The final study group comprised 53 patients (75% males; median age: 26 years; interquartile range: 17 to 39 years) from 29 proband-identified families. Thirty-three patients already have been reported in previous studies (4,9,11,(13)(14)(15).…”

Section: Methodsmentioning

confidence: 98%

“…Eight of them had AF or palpitations. An ICD was implanted in 9 patients because of a family history of SD, induction of VF at EPS, or both (9,13). Seven patients also received HQ, but it was soon interrupted in 5 patients.…”

Section: Patients Asymptomatic For Cardiac Arrest or Syncopementioning

confidence: 99%

Long-Term Follow-Up of Patients With Short QT Syndrome

Giustetto

Schimpf

Mazzanti

et al. 2011

Journal of the American College of Cardiology

281

211

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“…For example, in short QT syndrome caused by mutations in I Kr channel, some of the classical I Kr blockers fail to correct I Kr and the QT interval. 17,18 Mutant ionic channels may have altered binding properties and respond differently to drugs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Late Sodium Current by Mexiletine

Gao

Xue

et al. 2013

Circ: Arrhythmia and Electrophysiology

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Background-Timothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A(TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an I Na blocker, mexiletine, to improve clinical manifestations in TS. Methods and Results-A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening.Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C. Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father's oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470-490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT-RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late I Na with IC 50 of 17.6±1.9 µmol/L and attenuated brady-dependent QT prolongation and reduced QT-RR slope in the TS model using BayK 8644. Conclusions-Mexiletine shortened QTc, attenuated QT-RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late I Na . (Circ Arrhythm Electrophysiol. 2013;6:614-622.)Key Words: atrioventricular block ◼ late sodium current ◼ LQT8 ◼ mexiletine ◼ T wave alternans ◼ Timothy syndrome

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A novel mutation in the KCNH2 gene associated with short QT syndrome

Cited by 71 publications

References 28 publications

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

Long-Term Follow-Up of Patients With Short QT Syndrome

Inhibition of Late Sodium Current by Mexiletine

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