ArticleThe Journal of clinical investigation2003
Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 221 papers, 1 of them a synthesis that pooled it.
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Who cites it
221 citing papers in PubMed, 1 synthesis or guideline pooled it, 455 citations in OpenAlex.
- 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
- TGF-β1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.The Journal of allergy and clinical immunology · 2014Trial
- Neprilysin mediated cleavage of phospholamban dysregulates SERCA in heart failure.bioRxiv : the preprint server for biology · 2026Article
- Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.Nature communications · 2026Article
- Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.Signal transduction and targeted therapy · 2026Article
- Redox Imbalance and Genetic Mutations in Heart Failure: Synergistic Mechanisms and Therapeutic Strategies.Genes · 2026Review
- Promoting Autophagy Mitigates Stress-Induced Remodeling in Patient iPSC-CMs with the Phospholamban R9C Mutation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- From concept to application: Exploring the evolution and potential of DUBTAC technology.Acta pharmaceutica Sinica. B · 2026Review
- Humanized hiPSC Platforms for I/R Injury: Advancing Toward Precision Cardioprotection.Cardiovascular therapeutics · 2026Review
- Hypertrophic cardiomyopathy associate with aAME case reports · 2026Article
- Microprotein, macro-effect: DWORF as a therapeutic strategy in heart failure.Frontiers in cell and developmental biology · 2026Review
- The SERCA-PLN-DWORF axis in cardiometabolic disease: mechanisms and therapeutic perspectives.Cardiovascular diabetology · 2025Review
- Calcium handling remodeling in dilated cardiomyopathy: From molecular mechanisms to targeted therapies.Channels (Austin, Tex.) · 2025Review
- Targeting Calcium Regulation for Heart Failure and Arrhythmia Therapeutics: A Critical Review.Circulation · 2025Review
- Structural Elements of Dwarf Open Reading Frame Required for Activation of the Sarco-Endoplasmic Reticulum Calcium Pump.Biochemistry · 2025Article
- Calcium-dependent levels of phospholamban pentamer in native heart membranes reflect interactions of monomers with calcium-free SERCA2a.Archives of biochemistry and biophysics · 2025Article
- Emerging roles for microproteins as critical regulators of endoplasmic reticulum function and cellular homeostasis.Seminars in cell & developmental biology · 2025Review
- Modelling myocardial ischemia/reperfusion injury with inflammatory response in human ventricular cardiac organoids.Cell proliferation · 2025Article
- The endoplasmic reticulum luminal CaPNAS nexus · 2025Article
- Development of Small-molecule SERCA2a Stimulators: A Novel Class of Ino-lusitropic Agents.European cardiology · 2025Review
161 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
Abstract
In human disease and experimental animal models, depressed Ca(2+) handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy.
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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.