title: 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.
authors: Department of Engineering, Norfolk State University, Norfolk, VA 23504, USA.
authors: Makarand
authors: M
authors: Deo
authors: Yanfei
authors: Y
authors: Ruan
authors: Sandeep V
authors: SV
authors: Pandit
authors: Kushal
authors: K
authors: Shah
authors: Omer
authors: O
authors: Berenfeld
authors: Andrew
authors: A
authors: Blaufox
authors: Marina
authors: M
authors: Cerrone
authors: Sami F
authors: SF
authors: Noujaim
authors: Marco
authors: M
authors: Denegri
authors: José
authors: J
authors: Jalife
authors: Silvia G
authors: SG
authors: Priori
mesh_terms: D019943:Amino Acid Substitution; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D003198:Computer Simulation; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: C489457:KCNJ2 protein, human; D009124:Muscle Proteins; D024661:Potassium Channels, Inwardly Rectifying