ArticleCardiovascular research2015
A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia.
Article in Cardiovascular research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 3 of them syntheses 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
55 citing papers in PubMed, 3 syntheses or guidelines pooled it, 85 citations in OpenAlex.
- Geographical and Ethnic Heterogeneity in Genetic Dilated Cardiomyopathies.International journal of molecular sciences · 2026Pooled it
- Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta-analysis and systematic review.ESC heart failure · 2020Pooled it
- Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals.Clinical research in cardiology : official journal of the German Cardiac Society · 2017Pooled it
- Promoting Autophagy Mitigates Stress-Induced Remodeling in Patient iPSC-CMs with the Phospholamban R9C Mutation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PAD2 disturbs cardiomyocyte calcium homeostasis by citrullinating SERCA2a protein in hemorrhagic shock induced arrhythmia.The journal of trauma and acute care surgery · 2025Article
- G protein regulation by RGS proteins in the pathophysiology of dilated cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2025Review
- Genetic landscape of phospholamban cardiomyopathies.Frontiers in cell and developmental biology · 2025Review
- Genotype-Phenotype Insights of Inherited Cardiomyopathies-A Review.Medicina (Kaunas, Lithuania) · 2024Review
- Genetics of Dilated Cardiomyopathy.Annual review of medicine · 2024Review
- Article
- The Genetic Evaluation of Dilated Cardiomyopathy.Structural heart : the journal of the Heart Team · 2023Review
- Characterization of Skeletal Muscle Biopsy and Derived Myoblasts in a Patient Carrying Arg14del Mutation inCells · 2023Article
- Myofilament Alterations Associated with Human R14del-Phospholamban Cardiomyopathy.International journal of molecular sciences · 2023Article
- Phospholamban R14del disease: The past, the present and the future.Frontiers in cardiovascular medicine · 2023Review
- Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy.Journal of molecular and cellular cardiology · 2023Article
- Phospholamban p.Arg14del Cardiomyopathy: A Japanese Case Series.Internal medicine (Tokyo, Japan) · 2022Article
- Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired CaInternational journal of molecular sciences · 2022Article
- Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure.Nature communications · 2022Article
- Bioinformatics prediction of potential mechanisms and biomarkers underlying dilated cardiomyopathy.World journal of cardiology · 2022Article
- Characterization of the PLN p.Arg14del Mutation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.International journal of molecular sciences · 2021Article
Corrections and comments
- Commented on by
Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
aimsDepressed sarcoplasmic reticulum (SR) Ca(2+) cycling, a universal characteristic of human and experimental heart failure, may be associated with genetic alterations in key Ca(2+)-handling proteins. In this study, we identified a novel PLN mutation (R25C) in dilated cardiomyopathy (DCM) and investigated its functional significance in cardiomyocyte Ca(2+)-handling and contractility. METHODS AND
resultsExome sequencing identified a C73T substitution in the coding region of PLN in a family with DCM. The four heterozygous family members had implantable cardiac defibrillators, and three developed prominent ventricular arrhythmias. Overexpression of R25C-PLN in adult rat cardiomyocytes significantly suppressed the Ca(2+) affinity of SR Ca(2+)-ATPase (SERCA2a), resulting in decreased SR Ca(2+) content, Ca(2+) transients, and impaired contractile function, compared with WT-PLN. These inhibitory effects were associated with enhanced interaction of R25C-PLN with SERCA2, which was prevented by PKA phosphorylation. Accordingly, isoproterenol stimulation relieved the depressive effects of R25C-PLN in cardiomyocytes. However, R25C-PLN also elicited increases in the frequency of Ca(2+) sparks and waves as well as stress-induced aftercontractions. This was accompanied by increased Ca(2+)/calmodulin-dependent protein kinase II activity and hyper-phosphorylation of RyR2 at serine 2814.
conclusionThe findings demonstrate that human R25C-PLN is associated with super-inhibition of SERCA2a and Ca(2+) transport as well as increased SR Ca(2+) leak, promoting arrhythmogenesis under stress conditions. This is the first mechanistic evidence that increased PLN inhibition may impact both SR Ca(2+) uptake and Ca(2+) release activities and suggests that the human R25C-PLN may be a prognostic factor for increased ventricular arrhythmia risk in DCM carriers.
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.