ArticleJournal of the American College of Cardiology2013
Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.
Article in Journal of the American College of Cardiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
119 citing papers in PubMed, 1 synthesis or guideline pooled it, 185 citations in OpenAlex.
- One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2.Trends in cardiovascular medicine · 2023Pooled it
- Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.PloS one · 2018Trial
- Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation - Pathway Enrichment Analysis of GWAS Data.PloS one · 2016Trial
- The clinical pathophysiology of atrial fibrillation: outstanding questions from bedside to bench and back.Physiological reviews · 2026Review
- JP2 and JCN Crosstalk Abrogate MURF1-Mediated JCN Ubiquitination and Degradation in Cardiomyocytes.JACC. Basic to translational science · 2026Article
- The interaction between sarcoplasmic reticulum and mitochondria: a novel mechanism for cardiac arrhythmia.Frontiers in physiology · 2026Review
- Functional characterization of a novel JPH2 variant (p.R160H) associated with dilated cardiomyopathy.BMC cardiovascular disorders · 2025Article
- S165F mutation-induced Junctophilin-2 autoinhibition impairs CaCommunications biology · 2025Article
- Nonstructural Roles of Junctophilin-2 in the Heart.JACC. Basic to translational science · 2025Review
- Functional analysis of JPH2-knockout cardiomyocytes identifies ECCD as a novel indicator in a human cardiac modelJPH2.Stem cell research & therapy · 2025Article
- Long Non-coding RNA Involved in the Pathophysiology of Atrial Fibrillation.Cardiovascular drugs and therapy · 2025Review
- Time-dependent effect of FKBP12 loss in the development of dilated cardiomyopathy.The Journal of general physiology · 2025Article
- Atrial remodelling and dysfunction in hypertrophic cardiomyopathy: prognostic role and therapeutic target.Frontiers in cardiovascular medicine · 2025Review
- KFrontiers in physiology · 2025Article
- Aging-associated mechanisms of atrial fibrillation progression and their therapeutic potential.The journal of cardiovascular aging · 2024Article
- Enhanced CaJACC. Clinical electrophysiology · 2024Article
- Genetics and Pharmacogenetics of Atrial Fibrillation: A Mechanistic Perspective.JACC. Basic to translational science · 2024Review
- Structure, Function, and Regulation of the Junctophilin Family.Annual review of physiology · 2024Review
- Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old.International journal of molecular sciences · 2024Review
- hiPSC-derived cardiomyocytes as a model to study the role of small-conductance CaFrontiers in cell and developmental biology · 2024Review
59 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
13 authors at 4 institutions in 3 countries.
Funding
Abstract
objectivesThis study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF).
backgroundJPH2 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.
methodsScreening 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.
resultsPKI 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.
conclusionsOur 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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.