ArticleHuman molecular genetics2014
Recessive TTN truncating mutations define novel forms of core myopathy with heart disease.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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85 citing papers in PubMed, 189 citations in OpenAlex.
- Post-Exposure JNJ-26366821 Treatment Attenuates Systemic Inflammation and Limits Cardiotoxic Risk.Biomolecules · 2026Article
- Impact of CaInternational journal of molecular sciences · 2026Review
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (Circulation research · 2026Article
- Article
- Mechanically knocking out titin reveals protein tension loss as a trigger of muscle disease.Nature biomedical engineering · 2025Article
- HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model.Brain : a journal of neurology · 2025Article
- Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum.Annals of neurology · 2025Article
- The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes.Science advances · 2025Article
- Connecting intermediate phenotypes to disease using multi-omics in heart failure.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2025Article
- Congenital Titinopathies Linked to Mutations inInternational journal of molecular sciences · 2024Article
- Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy.American journal of medical genetics. Part A · 2024Article
- Taking on the Titin: Muscle imaging as a diagnostic marker of biallelicJournal of neuromuscular diseases · 2024Article
- Inferring disease course from differential exon usage in the wide titinopathy spectrum.Annals of clinical and translational neurology · 2024Article
- Connecting intermediate phenotypes to disease using multi-omics in heart failure.medRxiv : the preprint server for health sciences · 2024Article
- Identification of four TTN variants in three families with fetal akinesia deformation sequence.BMC medical genomics · 2024Article
- Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies.Scientific reports · 2024Review
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- Severe Form of Salih Myopathy Caused by Combination of Two Heterozygous TTN Mutations.Balkan journal of medical genetics : BJMG · 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
25 more citing papers are in PubMed but not listed here.
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24 authors at 14 institutions in 7 countries.
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Abstract
Core myopathies (CM), the main non-dystrophic myopathies in childhood, remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood. We analyzed a series of 23 families with congenital CM and primary heart disease using TTN M-line-targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17% patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional titin kinase domain in humans, leading to a severe antenatal phenotype. We establish that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding the TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.
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