ArticleHuman molecular genetics2021
Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 28 citations in OpenAlex.
- Clinical and experimental insights into hydroxychloroquine-associated electrical abnormalities and cardiomyopathy.European heart journal. Cardiovascular pharmacotherapy · 2026Article
- Lipid Metabolism as a Therapeutic Target in Arrhythmogenic Cardiomyopathy: Emerging Therapeutic Implications of Lipid-Lowering Therapy.Reviews in cardiovascular medicine · 2026Review
- Biologics for cardiovascular diseases: from bench to bedside.Signal transduction and targeted therapy · 2026Review
- Review
- The Role of Signalling Pathways in Myocardial Fibrosis in Hypertrophic Cardiomyopathy.Reviews in cardiovascular medicine · 2025Review
- Four cardiomyopathy patients with a heterozygous DSG2 p.Arg119Ter variant.Human genome variation · 2024Article
- Review
- Lactate regulates pathological cardiac hypertrophy via histone lactylation modification.Journal of cellular and molecular medicine · 2024Article
- Exploring the Therapeutic Potential of Gene Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy.Biomedicines · 2024Review
- Management Strategies in Arrhythmogenic Cardiomyopathy across the Spectrum of Ventricular Involvement.Biomedicines · 2023Review
- SARS-CoV-2 spike receptor-binding domain is internalized and promotes protein ISGylation in human induced pluripotent stem cell-derived cardiomyocytes.Scientific reports · 2023Article
- Nomogram for predicting cardiac death and heart transplantation in arrhythmogenic right ventricular cardiomyopathy.ESC heart failure · 2023Article
- Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models.Genes · 2023Review
- Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy.European heart journal open · 2023Article
- Modeling Reduced Contractility and Stiffness Using iPSC-Derived Cardiomyocytes Generated From Female Becker Muscular Dystrophy Carrier.JACC. Basic to translational science · 2023Article
- Disease modeling of desmosome-related cardiomyopathy using induced pluripotent stem cell-derived cardiomyocytes.World journal of stem cells · 2023Review
- Arrhythmogenic cardiomyopathy as a myogenic disease: highlights from cardiomyocytes derived from human induced pluripotent stem cells.Frontiers in physiology · 2023Review
- Article
- Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model forCirculation. Genomic and precision medicine · 2022Article
- Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes.Stem cell reports · 2022Article
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.
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