ArticleCirculation2014
Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype.
Article in Circulation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 185 papers, 2 of them syntheses that pooled it.
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Who cites it
185 citing papers in PubMed, 2 syntheses or guidelines pooled it, 332 citations in OpenAlex.
- Arrhythmogenic Right Ventricular Cardiomyopathy Post-Mortem Assessment: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity.Frontiers in pediatrics · 2021Pooled it
- Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.European journal of human genetics : EJHG · 2026Article
- Decreasing Microtubule Detyrosination Improves Cardiac Mechanics and Sodium Channel Function in Arrhythmogenic Cardiomyopathy.Circulation. Arrhythmia and electrophysiology · 2026Article
- Disease models and AAV therapies ofMolecular therapy. Advances · 2026Review
- Novel PKP2 compound heterozygous mutations causing neonatal early-onset arrhythmogenic cardiomyopathy: insights into the synergistic pathogenicity of biallelic inactivation.Functional & integrative genomics · 2026Article
- The role of iPSC research for insight into inherited arrhythmia conditions.Heart rhythm · 2025Review
- Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy: Mechanisms and Therapeutic Perspectives.Biomolecules · 2025Review
- Epigenetic regulation of electromechanical continuity might determine phenotypic heterogeneity in SCN5A mutation carriers in Brugada syndrome.Scientific reports · 2025Article
- Genetic Basis of Brugada Syndrome.Biomedicines · 2025Review
- Brugada syndrome.Nature reviews. Disease primers · 2025Review
- Computational Modeling of Effects ofCirculation. Arrhythmia and electrophysiology · 2025Article
- 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.Circulation · 2025Review
- The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies.International journal of molecular sciences · 2024Review
- Identifying the Pathogenic Variants in Heart Genes in Vietnamese Sudden Unexplained Death Victims by Next-Generation Sequencing.Diagnostics (Basel, Switzerland) · 2024Article
- The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity.International journal of molecular sciences · 2024Review
- Stem cell models of inherited arrhythmias.Nature cardiovascular research · 2024Review
- Engineered tissue geometry and Plakophilin-2 regulate electrophysiology of human iPSC-derived cardiomyocytes.APL bioengineering · 2024Article
- 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.Circulation · 2024Review
- Inherited Arrhythmias in the Pediatric Population: An Updated Overview.Medicina (Kaunas, Lithuania) · 2024Review
125 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundBrugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy. METHODS AND
resultsWe searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end.
conclusionsThis is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.
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