A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation

Xia, Min; Jin, Qingfeng; Bendahhou, Saı̈d; He, Yang; Larroque, Marie-Madeleine; Chen, Yiping; Qi-xin, Zhou; Yang, Yi‐Qing; Liu, Yi; Liu, Ban; Zhu, Qian; Zhou, Yanting; Lin, Jie; Liang, Bo; Li, Li; Dong, Xiongjian; Pan, Zhiwen; Wang, Rongrong; Wang, Haiying; Qiu, Weiliu; Xu, Wei; Eurlings, Petra M.H.; Barhanin, Jacques; Chen, Yihan

doi:10.1016/j.bbrc.2005.05.054

Cited by 338 publications

(215 citation statements)

References 32 publications

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“…However, to this date, the patient has not presented with ventricular tachycardia/ventricular fibrillation (VT/VF). Similar to the V93I mutation reported by Xia et al (13), the reason for the lack of ventricular arrhythmias remains unknown at this point. Nevertheless, as predicted by the 3D simulations (Fig.…”

Section: E299v Mutation Abolishes Inwardmentioning

confidence: 49%

“…Cotransfection of the WT and E299V plasmids mimicking the heterozygous substrate of the patients yielded an intermediate situation between WT and/ or E299V. The electrophysiological consequences of E299V are profoundly different from those of the D172N mutation that we reported as a unique KCNJ2 mutation linked to SQTS (3), as well as the V93I mutation reported by Xia et al (13) for a Chinese family with familial AF. Both D172N and V93I increase the outward current between −70 mV and −50 mV, thus causing sudden acceleration of the final phase of action potential repolarization that is responsible for an asymmetrically shaped T wave with a rapidly descending limb observed among mutation carriers.…”

Section: E299v Mutation Abolishes Inwardmentioning

confidence: 51%

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KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia

Deo

Ruan

Pandit

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

133

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We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K + channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward I K1 at potentials above −55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His-Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia. cellular electrophysiology | computer models | genetics | ion channels | channelopathies T he short QT syndrome (SQTS) is an inherited arrhythmogenic disorder characterized by a remarkably abbreviated repolarization and a predisposition to supraventricular and ventricular arrhythmias in the absence of detectable structural heart disease (1). Mutations found in SQTS patients in the genes encoding potassium channels cause "gain of function," whereas mutations found in the alpha 1C subunit of the voltage-dependent L-type Ca + channel (CACNA1C), the beta 2b subunit of the voltage dependent Ca 2+ channel (CACNB2B) and the alpha2/delta subunit 1 of the voltage dependent Ca 2+ channel (CACNA2D1) cause "loss of function" (1, 2). In 2005, we reported a mutation (D172N) in the strong inward rectifier K + channel protein (Kir2.1), which is coded by KCNJ2, in an SQTS patient: Functional characterization revealed that D172N shows an increased outward component of the inward rectifier current I K1 (3). Computer simulation demonstrated that D172N leads to a shortening of the QT interval and predisposes the heart to develop reentrant arrhythmias. Here we report a different KCNJ2 mutation (E299V) identified in a child with a re...

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Section: E299v Mutation Abolishes Inwardmentioning

confidence: 49%

Section: E299v Mutation Abolishes Inwardmentioning

confidence: 51%

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia

Deo

Ruan

Pandit

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

133

140

View full text Add to dashboard Cite

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“…In the other 11 investigated genes, no more mutations were identified in the 120 probands, except those that were reported earlier. 12,17,21 Multiple alignment of the Kv1.5 protein sequences across species A cross-species alignment of Kv1.5 protein sequences showed that the altered amino acids, except for Ala576, are completely conserved evolutionarily (Figure 3). in the net outward current compared with that generated by the expression of wild-type KCNA5 alone (Figure 4).…”

Section: Kcna5 Mutations In Af Kindreds and Patients With Idiopathic Afmentioning

confidence: 99%

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

et al. 2009

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Accumulating evidence reveals that genetic variants play pivotal roles in familial atrial fibrillation (AF). However, the molecular defects in most patients with AF remain to be identified. Here, we report on three novel KCNA5 mutations that were identified in 4 of 120 unrelated AF families. Among them, T527M was found in two AF families, and A576V and E610K in two other AF families, respectively. The mutations T527M and A576V were also detected in 2 and 1 of 256 patients with idiopathic AF, respectively. The same mutations were not observed in 200 secondary AF patients and 500 controls. Functional analyses revealed consistent loss-of-function effects of mutant KCNA5 proteins on the ultrarapidly activating delayed rectifier potassium currents. These findings expand the spectrum of mutations in KCNA5 linked to AF and provide new insight into the molecular mechanism involved in AF.

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“…A nonsense mutation in hKv1.5 (E375X) has recently been associated with one familial case of AF (15), which demonstrates the pertinence of analyzing this potassium channel in patients suffering from AF. In addition to the hKv1.5 gene, to date, only a few other genes, KvLQT1 (16,17), Kir2.1 (18) and MiRP1 (19), have been found to be associated with AF in a very limited number of patients. Of note, all these genes encode for subunits of cardiac potassium channels, and all the identified mutations potentially shorten the atrial action potential duration and effective refractory period.…”

Section: Discussionmentioning

confidence: 99%