Mutation E169K in Junctophilin-2 Causes Atrial Fibrillation Due to Impaired RyR2 Stabilization

• Published in: Journal of the American College of Cardiology Vol. 62; no. 21; pp. 2010 - 2019
• Main Authors: Beavers, David L., BS, Wang, Wei, PhD, Ather, Sameer, MD, PhD, Voigt, Niels, MD, Garbino, Alejandro, MD, PhD, Dixit, Sayali S., PhD, Landstrom, Andrew P., MD, PhD, Li, Na, PhD, Wang, Qiongling, PhD, Olivotto, Iacopo, MD, Dobrev, Dobromir, MD, Ackerman, Michael J., MD, PhD, Wehrens, Xander H.T., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 19.11.2013; Elsevier; Elsevier Limited
• Subjects: Animals; atrial fibrillation; Atrial Fibrillation - genetics; Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Biological and medical sciences; calcium; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Cardiovascular; Disease Models, Animal; DNA - genetics; DNA Mutational Analysis; Heart; Internal Medicine; junctophilin; Laboratory animals; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mortality; Mutation; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Patch-Clamp Techniques; Proteins; Rodents; ryanodine receptor; sarcoplasmic reticulum; Studies; NCX; junctional membrane complex; junctophilin; pseudoknock-in; sarcoplasmic reticulum; Ca 2; atrial fibrillation; JPH2; ryanodine receptor; Tg; delayed afterdepolarizations; transgenic; Na +/Ca 2+ exchanger; WT; SR; NTg; RyR2; early afterdepolarizations; JMC; calcium; AF; DAD; EAD; junctophilin-2; PKI; HCM; ryanodine receptor type 2; hypertrophic cardiomyopathy; wild type; nontransgenic; Ca2; Arrhythmia; Stabilization; Heart disease; Atrial fibrillation; Cause; Cardiovascular disease; Circulatory system; Mutation; Cardiology; Excitability disorder; Na(+)/Ca(2+) exchanger; Ca(2+)
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2013.06.052

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) Ca2+ handling and modulation of ryanodine receptor Ca2+ channels (RyR2). Whereas defective RyR2-mediated Ca2+ 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 Ca2+ 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. Ca2+ 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 Ca2+ 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 Ca2+ leak and atrial arrhythmias, representing a potential novel therapeutic target for AF.