title: Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.
abstract: OBJECTIVE
  This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF).
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: David L
authors: DL
authors: Beavers
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Wei
authors: W
authors: Wang
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Sameer
authors: S
authors: Ather
authors: Institute of Pharmacology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors: Niels
authors: N
authors: Voigt
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Alejandro
authors: A
authors: Garbino
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Sayali S
authors: SS
authors: Dixit
authors: 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.
authors: Andrew P
authors: AP
authors: Landstrom
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Na
authors: N
authors: Li
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Qiongling
authors: Q
authors: Wang
authors: Careggi University Hospital, University of Florence, Florence, Italy.
authors: Iacopo
authors: I
authors: Olivotto
authors: Institute of Pharmacology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors: Dobromir
authors: D
authors: Dobrev
authors: 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.
authors: Michael J
authors: MJ
authors: Ackerman
authors: Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
authors: Xander H T
authors: XHT
authors: Wehrens
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques
chemical_list: D008565:Membrane Proteins; C412507:junctophilin; D004247:DNA
keywords: 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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