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

ABSTRACT: 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 IK1 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.

SUBMITTER: Deo M

PROVIDER: S-EPMC3600465 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Deo Makarand M Ruan Yanfei Y Pandit Sandeep V SV Shah Kushal K Berenfeld Omer O Blaufox Andrew A Cerrone Marina M Noujaim Sami F SF Denegri Marco M Jalife José J Priori Silvia G SG

Proceedings of the National Academy of Sciences of the United States of America 20130225 11

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 abnorma ...[more]

PMID: 23440193

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Project description:Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (I NaL , I Ks , and I Kr ) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

Dataset Information

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

Publications

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

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