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

Publication ,  Journal Article
Beavers, DL; Wang, W; Ather, S; Voigt, N; Garbino, A; Dixit, SS; Landstrom, AP; Li, N; Wang, Q; Olivotto, I; Dobrev, D; Ackerman, MJ; Wehrens, XHT
Published in: J Am Coll Cardiol
November 19, 2013

OBJECTIVES: 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.

Duke Scholars

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Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

November 19, 2013

Volume

62

Issue

21

Start / End Page

2010 / 2019

Location

United States

Related Subject Headings

  • Patch-Clamp Techniques
  • Myocytes, Cardiac
  • Mutation
  • Mice, Knockout
  • Mice
  • Membrane Proteins
  • Disease Models, Animal
  • DNA Mutational Analysis
  • DNA
  • Cardiovascular System & Hematology
 

Citation

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Beavers, D. L., Wang, W., Ather, S., Voigt, N., Garbino, A., Dixit, S. S., … Wehrens, X. H. T. (2013). Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol, 62(21), 2010–2019. https://doi.org/10.1016/j.jacc.2013.06.052
Beavers, David L., Wei Wang, Sameer Ather, Niels Voigt, Alejandro Garbino, Sayali S. Dixit, Andrew P. Landstrom, et al. “Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.J Am Coll Cardiol 62, no. 21 (November 19, 2013): 2010–19. https://doi.org/10.1016/j.jacc.2013.06.052.
Beavers DL, Wang W, Ather S, Voigt N, Garbino A, Dixit SS, et al. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol. 2013 Nov 19;62(21):2010–9.
Beavers, David L., et al. “Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.J Am Coll Cardiol, vol. 62, no. 21, Nov. 2013, pp. 2010–19. Pubmed, doi:10.1016/j.jacc.2013.06.052.
Beavers DL, Wang W, Ather S, Voigt N, Garbino A, Dixit SS, Landstrom AP, Li N, Wang Q, Olivotto I, Dobrev D, Ackerman MJ, Wehrens XHT. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol. 2013 Nov 19;62(21):2010–2019.
Journal cover image

Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

November 19, 2013

Volume

62

Issue

21

Start / End Page

2010 / 2019

Location

United States

Related Subject Headings

  • Patch-Clamp Techniques
  • Myocytes, Cardiac
  • Mutation
  • Mice, Knockout
  • Mice
  • Membrane Proteins
  • Disease Models, Animal
  • DNA Mutational Analysis
  • DNA
  • Cardiovascular System & Hematology