ArticleOpen biology2016
Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.
Article in Open biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Structure of theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Molecular basis of Fab-dependent IgA antibody recognition by gut-bacterial metallopeptidases.The EMBO journal · 2025Article
- A pathogenic titin missense mutation in hiPSC-derived cardiomyocytes predisposes to ventricular fibrillation in acute ST-segment elevation myocardial infarction.Frontiers in cardiovascular medicine · 2025Article
- Split Luciferase Molecular Tension Sensors for Bioluminescent Readout of Mechanical Forces in Biological Systems.ACS sensors · 2024Article
- Molecular insights into titin's A-band.Journal of muscle research and cell motility · 2023Article
- Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation.Journal of structural biology · 2023Article
- Facile detection of mechanical forces across proteins in cells with STReTCh.Cell reports methods · 2022Article
- Pairwise sequence similarity mapping with PaSiMap: Reclassification of immunoglobulin domains from titin as case study.Computational and structural biotechnology journal · 2022Article
- Single-Molecule Force Spectroscopy Studies of Missense Titin Mutations That Are Likely Causing Cardiomyopathy.Langmuir : the ACS journal of surfaces and colloids · 2021Article
- Protein nanomechanics in biological context.Biophysical reviews · 2021Review
- Titin N2A Domain and Its Interactions at the Sarcomere.International journal of molecular sciences · 2021Review
- The N2A region of titin has a unique structural configuration.The Journal of general physiology · 2021Article
- Arrhythmogenic Cardiomyopathy: Molecular Insights for Improved Therapeutic Design.Journal of cardiovascular development and disease · 2020Review
- Elastic domains of giant proteins in striated muscle: Modeling compliance with rulers.The Journal of general physiology · 2019Article
- Twitchin kinase inhibits muscle activity.Molecular biology of the cell · 2017Article
- High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation.PloS one · 2017Article
Corrections and comments
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Authors and funding
14 authors at 8 institutions in 3 countries.
Funding
Abstract
Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.
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Registered trials
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