Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family

Zhang, Su; Yin, Ke; Ren, Xiang; Wang, Pengyun; Zhang, Shirong; Cheng, Lan; Yang, Jing; Liu, Jingyu; Liu, Mugen; Wang, Qing Kenneth

doi:10.1186/1471-2350-9-24

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…Heterozygous expression of mutated subunits and wild-type subunits in equal molar ratios results in general in a milder biophysical phenotype (more close to the wild-type phenotype). This is in line with a milder clinical phenotype generally reported for heterozygous carriers of LQTS mutations compared to individuals with homozygous genotypes (Priori et al, 1998; Jackson et al, 2014; Zhang et al, 2008). Moreover, for different mutations different biophysical effects of the mutations could be dominant or recessive: For S225L and L251A, heterozygous expression in the presence of KCNE1 partially or completely restores wild-type like V 50 , whereas heterozygous expression does not improve closing kinetics compared to homozygous expression.…”

Section: Discussionsupporting

confidence: 87%

Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Liin

Larsson

Barro-Soria

et al. 2016

eLife

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About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.DOI: http://dx.doi.org/10.7554/eLife.20272.001

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Section: Discussionsupporting

confidence: 87%

Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Liin

Larsson

Barro-Soria

et al. 2016

eLife

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“…I Ks is an important outward potassium current regulating late repolarisation of action potentials (APs) in cardiac cells. Abnormalities in I Ks have been found in various cardiac diseases including long QT (Lundby et al 2007; Zhang et al 2008 b ) and short QT (Bellocq et al 2004) syndromes. In a previous simulation study it has been shown that increased I Ks due to a gain‐in‐function (V307L) KCNQ1 mutation in Short QT‐2 syndrome dramatically abbreviates human ventricular AP duration (APD) and augments intra‐ventricular heterogeneity, leading to increased ventricular susceptibility to arrhythmia (Zhang et al 2008 a ).…”

Section: Introductionmentioning

confidence: 99%

Pro‐arrhythmogenic effects of the S140G KCNQ1 mutation in human atrial fibrillation – insights from modelling

Kharche

Adeniran

Stott

et al. 2012

The Journal of Physiology

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Key points• A previous study has identified a gene mutation (KCNQ1 S140G) in some patients with a familial form of atrial fibrillation, one of the most common cardiac rhythm disturbances causing morbidity and mortality. A causal link between the mutation and genesis of atrial fibrillation has not yet been directly demonstrated.• Increased I Ks arising from the KCNQ1 S140G mutation abbreviated atrial action potential duration (APD) and effective refractory period (ERP) and flattened APD and ERP restitution curves. It reduced atrial conduction velocity at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves.• The mutation increased tissue susceptibility for initiation and maintenance of atrial arrhythmias.• The mutation stabilizes and accelerates re-entrant excitation waves, leading to rapid and sustained re-entry.• This study provides novel insights towards understanding the mechanisms underlying the pro-arrhythmic effects of the KCNQ1 S140G mutation.Abstract Functional analysis has shown that the missense gain-in-function KCNQ1 S140G mutation associated with familial atrial fibrillation produces an increase of the slow delayed rectifier potassium current (I Ks ). Through computer modelling, this study investigated mechanisms by which the KCNQ1 S140G mutation promotes and perpetuates atrial fibrillation. In simulations, Courtemanche et al.'s model of human atrial cell action potentials (APs) was modified to incorporate experimental data on changes of I Ks induced by the KCNQ1 S140G mutation. The cell models for wild type (WT) and mutant type (MT) I Ks were incorporated into homogeneous multicellular 2D and 3D tissue models. Effects of the mutation were quantified on AP profile, AP duration (APD) restitution, effective refractory period (ERP) restitution, and conduction velocity (CV) restitution. Temporal and spatial vulnerabilities of atrial tissue to genesis of re-entry were computed. Dynamic behaviours of re-entrant excitation waves (lifespan (LS), tip meandering patterns and dominant frequency) in 2D and 3D models were characterised. It was shown that the KCNQ1 S140G mutation abbreviated atrial APD and ERP and flattened APD and ERP restitution curves. It reduced atrial CV at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves. Although it increased slightly tissue temporal vulnerability for initiating re-entry, it reduced markedly the minimal substrate size necessary for sustaining re-entry (increasing the tissue spatial vulnerability). In the 2D and 3D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. In the 3D model, scroll waves under the mutation condition MT conditions also degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, increased I Ks due to the KCNQ1 S140G mutation increases atrial susceptibility to arrhythmia due to increased tissu...

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“…Mutations K V 7.1-T322A and K V 7.1-T322M cause a severe loss of function, as shown here (Figure 3), and were reported to be associated with LQT1 36, 40, 41. Both mutations can be expected to disrupt the H-bond because the H-donor in the threonine side chain is eliminated by the mutation.…”

Section: Discussionmentioning

confidence: 63%

Structural interplay of KV7.1 and KCNE1 is essential for normal repolarization and is compromised in short QT syndrome 2 (KV7.1-A287T)

Rothenberg

Piccini

Wrobel

et al. 2016

HeartRhythm Case Reports

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Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family

Cited by 16 publications

References 32 publications

Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Pro‐arrhythmogenic effects of the S140G KCNQ1 mutation in human atrial fibrillation – insights from modelling

Structural interplay of KV7.1 and KCNE1 is essential for normal repolarization and is compromised in short QT syndrome 2 (KV7.1-A287T)

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