ArticleJCI insight2019
Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 41 citations in OpenAlex.
- Desmoplakin Loss Leads to PKC- and Src-Mediated Contractile Dysfunction in Cardiomyocytes.Circulation research · 2026Article
- Human-Induced Pluripotent Stem Cell Models for Amyloid Cardiomyopathy: From Mechanistic Insights to Therapeutic Discovery.Journal of cardiovascular development and disease · 2025Review
- Induced Pluripotent Stem Cells in Cardiomyopathy: Advancing Disease Modeling, Therapeutic Development, and Regenerative Therapy.International journal of molecular sciences · 2025Review
- Engineered heart tissue: Design considerations and the state of the art.Biophysics reviews · 2024Review
- Article
- Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies.Scientific reports · 2024Review
- Prevention of Protease-Induced Degradation of Desmoplakin via Small Molecule Binding.Journal of personalized medicine · 2024Article
- Molecular Pathways and Animal Models of Arrhythmias.Advances in experimental medicine and biology · 2024Article
- Chronic diastolic stretch unmasks conduction defects in an in vitro model of arrhythmogenic cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2023Article
- Evaluation of Porcine Psoas Major as a Scaffold Material for Engineered Heart Tissues.Tissue engineering. Part C, Methods · 2023Article
- Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models.Genes · 2023Review
- Calpain Regulation and Dysregulation-Its Effects on the Intercalated Disk.International journal of molecular sciences · 2023Review
- Disease modeling of desmosome-related cardiomyopathy using induced pluripotent stem cell-derived cardiomyocytes.World journal of stem cells · 2023Review
- Animal Disease Models and Patient-iPS-Cell-Derived In Vitro Disease Models for Cardiovascular Biology-How Close to Disease?Biology · 2023Review
- Generation of human iPSC line from an arrhythmogenic cardiomyopathy patient with a DSP protein-truncating variant.Stem cell research · 2023Article
- HumanizedCells · 2022Article
- Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction.International journal of molecular sciences · 2022Review
- Functional investigation of two simultaneous or separately segregating DSP variants within a single family supports the theory of a dose-dependent disease severity.Experimental dermatology · 2022Article
- Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (Cardiogenetics · 2022Article
- Genetic predisposition study of heart failure and its association with cardiomyopathy.The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology · 2022Review
Corrections and comments
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Authors and funding
22 authors at 7 institutions in 1 country.
Funding
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder with variable genetic etiologies. Here we focused on understanding the precise molecular pathology of a single clinical variant in DSP, the gene encoding desmoplakin. We initially identified a novel missense desmoplakin variant (p.R451G) in a patient diagnosed with biventricular ACM. An extensive single-family ACM cohort was assembled, revealing a pattern of coinheritance for R451G desmoplakin and the ACM phenotype. An in vitro model system using patient-derived induced pluripotent stem cell lines showed depressed levels of desmoplakin in the absence of abnormal electrical propagation. Molecular dynamics simulations of desmoplakin R451G revealed no overt structural changes, but a significant loss of intramolecular interactions surrounding a putative calpain target site was observed. Protein degradation assays of recombinant desmoplakin R451G confirmed increased calpain vulnerability. In silico screening identified a subset of 3 additional ACM-linked desmoplakin missense mutations with apparent enhanced calpain susceptibility, predictions that were confirmed experimentally. Like R451G, these mutations are found in families with biventricular ACM. We conclude that augmented calpain-mediated degradation of desmoplakin represents a shared pathological mechanism for select ACM-linked missense variants. This approach for identifying variants with shared molecular pathologies may represent a powerful new strategy for understanding and treating inherited cardiomyopathies.
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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.