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J Am Coll Cardiol. 2013 Nov 19;62(21):2010-9. doi: 10.1016/j.jacc.2013.06.052. Epub 2013 Aug 21.

Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.

Author information

Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
Institute of Pharmacology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
Depts of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics/Divisions of Cardiovascular Diseases and Pediatric Cardiology; Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
Careggi University Hospital, University of Florence, Florence, Italy.
Contributed equally



This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF).


JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca(2+) handling and modulation of ryanodine receptor Ca(2+) channels (RyR2). Whereas defective RyR2-mediated Ca(2+) release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias.


Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudoknock-in (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation.


PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF than wild type (WT)-PKI mice, whereas A399S-PKI mice expressing a hypertrophic cardiomyopathy-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca(2+) release events. These changes were attributed to reduced binding of E169K-JPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca(2+) spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients and an increased frequency of spontaneous Ca(2+) release events.


Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2/RyR2 ratios can promote SR Ca(2+) leak and atrial arrhythmias, representing a potential novel therapeutic target for AF.


AF; Ca(2+); DAD; EAD; HCM; JMC; JPH2; NCX; NTg; Na(+)/Ca(2+) exchanger; PKI; RyR2; SR; Tg; WT; atrial fibrillation; calcium; delayed afterdepolarizations; early afterdepolarizations; hypertrophic cardiomyopathy; junctional membrane complex; junctophilin; junctophilin-2; nontransgenic; pseudoknock-in; ryanodine receptor type 2; ryanodine receptor; sarcoplasmic reticulum; transgenic; wild type

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