Expression of a Common LQT1 Mutation in Five Apparently Unrelated Families in a Regional Inherited Arrhythmia Clinic

Gray, Christopher; Gula, Lorne J.; Klein, George J.; Skanes, Allan C.; Yee, Raymond; Sy, Raymond W.; Salisbury, Benjamin A.; Wong, Jorge; Chattha, Ishvinder; Subbiah, Rajesh N.; Krahn, Andrew D.

doi:10.1111/j.1540-8167.2009.01626.x

Cited by 5 publications

(1 citation statement)

References 24 publications

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“…Such a regional predominance in frequency is associated with LQT1. [23][24][25] There is a report that describes a large Dutch family with a founder mutation that uniquely overlaps those of LQT3, BrS, and progressive cardiac conduction defects. 26 The subtropical Okinawa Islands are located 2,000 km south of mainland Japan between the East China Sea and the Pacific Ocean.…”

Section: Prevalence Of Lqt3mentioning

confidence: 99%

High Prevalence of the <i>SCN5A</i> E1784K Mutation in School Children With Long QT Syndrome Living on the Okinawa Islands

Takahashi

Shimizu

Miyake

et al. 2014

Circ J

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Section: Prevalence Of Lqt3mentioning

confidence: 99%

High Prevalence of the <i>SCN5A</i> E1784K Mutation in School Children With Long QT Syndrome Living on the Okinawa Islands

Takahashi

Shimizu

Miyake

et al. 2014

Circ J

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Assessment of Genetic Causes of Cardiac Arrest

Bennett

Sanatani

Chakrabarti

et al. 2013

Canadian Journal of Cardiology

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Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation

Synková

Bébarová

Andršová

et al. 2021

Sci Rep

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The variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to β-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under β-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under β-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to β-blocker therapy.

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Expression of a Common LQT1 Mutation in Five Apparently Unrelated Families in a Regional Inherited Arrhythmia Clinic

Cited by 5 publications

References 24 publications

High Prevalence of the <i>SCN5A</i> E1784K Mutation in School Children With Long QT Syndrome Living on the Okinawa Islands

High Prevalence of the <i>SCN5A</i> E1784K Mutation in School Children With Long QT Syndrome Living on the Okinawa Islands

Assessment of Genetic Causes of Cardiac Arrest

Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation

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