ArticleBasic research in cardiology2021
Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant.
Article in Basic research in cardiology, 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, 29 citations in OpenAlex.
- Functional analysis ofMolecular therapy. Nucleic acids · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Injectable therapeutic system incorporating neurogenesis-programmed stem cells concomitantly promoting muscle regeneration treats stress urinary incontinence.Nature communications · 2025Article
- Mechanosensitive biochemical imprinting of the talin interaction with DLC1 regulates RhoA activity and cardiomyocyte remodeling.Science advances · 2025Article
- Filamin C dimerisation is regulated by HSPB7.Nature communications · 2025Article
- An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.Scientific reports · 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
- Integrative proteomic and metabolomic elucidation of cardiomyopathy with in vivo and in vitro models and clinical samples.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström syndrome cardiomyopathy.Disease models & mechanisms · 2024Article
- Allelic heterogeneity of TTNtv dilated cardiomyopathy can be modeled in adult zebrafish.JCI insight · 2024Article
- Common and Key Differential Pathogenic Pathways in Desminopathy and Titinopathy.International journal of medical sciences · 2024Article
- 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
- Transcriptome studies of inherited dilated cardiomyopathies.Mammalian genome : official journal of the International Mammalian Genome Society · 2023Review
- Alterations in oligodendrocyte transcriptional networks reveal region-specific vulnerabilities to neurological disease.iScience · 2023Article
- Quantitative Image Processing for Three-Dimensional Episcopic Images of Biological Structures: Current State and Future Directions.Biomedicines · 2023Review
- Article
- Structural and signaling proteins in the Z-disk and their role in cardiomyopathies.Frontiers in physiology · 2023Review
- A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart.Cardiovascular research · 2022Article
- Discerning the Ambiguous Role of MissenseJournal of personalized medicine · 2022Article
- Protein Quality Control at the Sarcomere: Titin Protection and Turnover and Implications for Disease Development.Frontiers in physiology · 2022Review
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Authors and funding
21 authors at 6 institutions in 3 countries.
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Abstract
Titin truncating variants are a well-established cause of cardiomyopathy; however, the role of titin missense variants is less well understood. Here we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported titin A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Heterozygous and homozygous mice carrying the titin A178D missense variant were characterised in vivo by echocardiography. Heterozygous mice had no detectable phenotype at any time point investigated (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the foetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified downregulation of telethonin and four-and-a-half LIM domain 2, as well as the upregulation of heat shock proteins and myeloid leukaemia factor 1. Loss of telethonin from the cardiac Z-disc was accompanied by proteasomal degradation; however, unfolded telethonin accumulated in the cytoplasm, leading to a proteo-toxic response in the mice.We show that the titin A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism: because the titin A178D variant abolishes binding of telethonin, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of telethonin by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.
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