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![Titin isoforms and mapped disease-associated missense mutations. Titin isoforms assembled from the metatranscript, cardiac N2BA, cardiac N2B, skeletal muscle N2A, Novex3 and Cronos transcripts (from top to bottom). See text for details. Missense mutations causing DCM, HCM, ARVC, RCM and myopathy are shown by vertical lines mapped on the protein domains where they occur. Missense mutations downloaded from the TITINdb (http://fraternalilab.kcl.ac.uk/TITINdb/), see Laddach et al. [71]. Domain colors: red: Ig domains, white: Fn domains, green: Z-repeats, yellow: PEVK sequence, blue: unique sequences](publication/332051638/figure/fig1/AS:941431162159104@1601466088001/Titin-isoforms-and-mapped-disease-associated-missense-mutations-Titin-isoforms-assembled.png)
Titin isoforms and mapped disease-associated missense mutations. Titin isoforms assembled from the metatranscript, cardiac N2BA, cardiac N2B, skeletal muscle N2A, Novex3 and Cronos transcripts (from top to bottom). See text for details. Missense mutations causing DCM, HCM, ARVC, RCM and myopathy are shown by vertical lines mapped on the protein domains where they occur. Missense mutations downloaded from the TITINdb (http://fraternalilab.kcl.ac.uk/TITINdb/), see Laddach et al. [71]. Domain colors: red: Ig domains, white: Fn domains, green: Z-repeats, yellow: PEVK sequence, blue: unique sequences
Source publication
The introduction of next-generation sequencing technology has revealed that mutations in the gene that encodes titin (TTN) are linked to multiple skeletal and cardiac myopathies. The most prominent of these myopathies is dilated cardiomyopathy (DCM). Over 60 genes are linked to the etiology of DCM, but by far, the leading cause of DCM is mutations...
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Background:
Approximately one-third of cases of dilated cardiomyopathy (DCM) are caused by genetic mutations. With new sequencing technologies, numerous variants have been associated with this inherited cardiomyopathy, however the prevalence and genotype-phenotype correlations in different ethnic cohorts remain unclear. This study aimed to investi...
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Citations
... The patient has 2 children with different mothers. (33). Furthermore, TTN variants located in the I-band are more tolerated since many exons on this area are subject to alternative splicing (7, 33). ...
This case report details the identification of a novel likely pathogenic splicing variant in the TTN gene, associated with dilated cardiomyopathy (DCM), in a 42-year-old male patient presenting with early-onset heart failure and reduced ejection fraction. DCM is a nonischemic heart condition characterized by left biventricular dilation and systolic dysfunction, with approximately one-third of cases being familial and often linked to genetic mutations. The TTN gene, encoding the largest human protein essential for muscle contraction and sarcomere structure, is implicated in about 25% of DCM cases through mutations, especially truncating variants. Our investigation revealed a previously unreported G > C mutation at the splice acceptor site in intron 356 of TTN, confirmed by Sanger sequencing and not found in population databases, suggesting a novel contribution to the understanding of DCM etiology. The case emphasizes the critical role of the TTN gene in cardiac function and the genetic complexity underlying DCM. A comprehensive literature review highlighted the prevalence and significance of splice variants in the TTN gene, particularly those affecting the titin A-band, which is known for its role in muscle contraction and stability. This variant's identification underscores the importance of genetic screening in patients with DCM, offering insights into the disease's familial transmission and potential therapeutic targets. Our findings contribute to the expanding knowledge of genetic factors in DCM, demonstrating the necessity of integrating genetic diagnostics in cardiovascular medicine. This case supports the growing evidence linking splicing mutations in specific regions of the TTN gene to DCM development and underscores the importance of genetic counseling and testing in managing heart disease.
... The TTN protein is in a very critical position in our protein network. Studies have shown that TTN gene mutations are associated with multiple skeletal myopathies and cardiomyopathies, the most prominent of which is dilated cardiomyopathy 17 . TTN protein can be modi ed in a variety of ways to perform different functions. ...
Sarcopenia is a progressive and systemic skeletal muscle disease that involves an accelerated loss of muscle mass and function. It is associated with increased adverse outcomes, including falls, functional decline, frailty, and death. With the advent of an aging society, sarcopenia has become a focus of intensive research. However, the molecular signaling pathways and phosphosignaling transduction changes in patients with sarcopenia are still unclear. To this end, we performed a quantitative mass spectrometry-based phosphoproteomics study on 6 patients with sarcopenia and 6 normal elderly subjects, and quantitatively analyzed 6163 phosphorylation sites of 2253 proteins. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that many phosphorylated proteins are involved in sarcomere organization and muscle filament sliding pathways. Kinase prediction analysis suggests that serine/threonine protein kinases VRK1, VRK2, etc. may play an important role in abnormal muscle metabolism. This study greatly expands our understanding of this disease by performing phosphoproteomics analysis on patients with sarcopenia. These findings provide a basis for the study of other age-related diseases.
... Understanding the underlying intricacies is vital, since the resulting parameters such as cell stiffness are emerging players in multiple pathologies [64]. This includes several examples like for instance cancer progression [65,66], cardiomyopathies and musculoskeletal disorders [67][68][69], as well as aging [70,71]. Along this line, the role of cell biomechanical compliance in pathophysiological context is increasingly acknowledged [72][73][74][75]. ...
Bladder cells face a challenging biophysical environment: mechanical cues originating from urine flow and regular contraction to enable the filling voiding of the organ. To ensure functional adaption, bladder cells rely on high biomechanical compliance, nevertheless aging or chronic pathological conditions can modify this plasticity. Obviously the cytoskeletal network plays an essential role, however the contribution of other, closely entangled, intracellular organelles is currently underappreciated. The endoplasmic reticulum (ER) lies at a crucial crossroads, connected to both nucleus and cytoskeleton. Yet, its role in the maintenance of cell mechanical stability is less investigated. To start exploring these aspects, T24 bladder cancer cells were treated with the ER stress inducers brefeldin A (10-40nM BFA, 24 h) and thapsigargin (0.1-100nM TG, 24 h). Without impairment of cell motility and viability, BFA and TG triggered a significant subcellular redistribution of the ER; this was associated with a rearrangement of actin cytoskeleton. Additional inhibition of actin polymerization with cytochalasin D (100nM CytD) contributed to the spread of the ER toward cell periphery, and was accompanied by an increase of cellular stiffness (Young´s modulus) in the cytoplasmic compartment. Shrinking of the ER toward the nucleus (100nM TG, 2 h) was related to an increased stiffness in the nuclear and perinuclear areas. A similar short-term response profile was observed also in normal human primary bladder fibroblasts. In sum, the ER and its subcellular rearrangement seem to contribute to the mechanical properties of bladder cells opening new perspectives in the study of the related stress signaling cascades.
... 从而特异性调节弹性 PEVK 区域的刚度 [ [98,110] ...
Titin, the largest known protein in the body expressed in three isoforms (N2A, N2BA and N2B), is essential for muscle structure, force generation, conduction and regulation. Since the 1950s, muscle contraction mechanisms have been explained by the sliding filament theory involving thin and thick muscle filaments, while the contribution of cytoskeleton in force generation and conduction was ignored. With the discovery of insoluble protein residues and large molecular weight proteins in muscle fibers, the third myofilament, titin, has been identified and attracted a lot of interests. The development of single molecule mechanics and gene sequencing technology further contributed to the extensive studies on the arrangement, structure, elastic properties and components of titin in sarcomere. Therefore, this paper reviews the structure, isforms classification, elastic function and regulatory factors of titin, to provide better understanding of titin.
... Some variants that may be associated with IUGR were screened by WES, such as the TTN variants. TTN variants have been reported to be linked to multiple skeletal and cardiac myopathies [24]. Genetic analysis results revealed that the TTN missense variants in case 1 and case 2 were inherited from the father and were homozygous due to UPD of chromosome 2. ...
Uniparental disomy (UPD) is when all or part of the homologous chromosomes are inherited from only one of the two parents. Currently, UPD has been reported to occur for almost all chromosomes. In this study, we report two cases of UPD for chromosome 2 (UPD2) encountered during prenatal diagnosis. The ultrasound findings of the fetuses from two unrelated families showed intrauterine growth restriction. The karyotype analyses were normal. The two fetuses both had complete paternal chromosome 2 uniparental disomy detected by whole-exome sequencing, but their clinical outcomes were significantly different, with fetal arrest in case 1 and birth in case 2. In this report, we analyzed and discussed the phenotypes of the fetuses in these two cases and reviewed the literature on UPD2.
... High frequency gene analysis revealed several important genes including TP53, TTN, and MUC16. The TTN gene encodes myosin (Titin), which is expressed mainly in skeletal and cardiac muscle tissues and can cause a variety of cardiomyopathies when mutated [21,22]. MUC16 is a protein-coding gene associated with ovarian cysts and clear cell adenocarcinoma. ...
The genomic events associated with poor outcomes in other ocular tumors are poorly understood, except for the in-depth study of the retinoblastoma Rb gene. We investigated 48 patients with ocular tumors, using three types of samples - cancerous tissue, paraneoplastic tissue, and peripheral blood. We employed combined exome and transcriptome analysis to search for high-frequency mutated genes and susceptibility genes in ocular tumors. Our exon sequencing analysis identified four clear causative genes ( TP53, PTCH1, SMO, BAP1 ), most of which were associated with basal cell carcinoma. Two mutations in BAP1 were clearly associated with choroidal melanoma, and no clear causative loci were found in other cancer types. Our susceptibility gene analysis identified hotspot genes such as RUNX1, APC, IDH2 , and BRCA2 . High-frequency gene analysis identified TP53 , TTN , and MUC16 genes, among others. Transcriptome analysis identified TOP2A and ZWINT genes were upregulated in all samples, while CFD , ELANE , HBA1 , and HBB were downregulated. Our KEGG enrichment analysis indicated that the PI3K-Akt signaling pathway and transcriptional misregulation in cancer may be involved in the process of ocular tumorigenesis. We found that TP53 is clearly involved in ocular tumorigenesis, especially in basal cell carcinoma, and its PI3K-Akt signaling pathway may be an essential pathway involved in ocular tumorigenesis. Additionally, RUNX1 , SMO , TOP2A , and ZWINT are highly likely to be involved in ocular tumorigenesis, and subsequent functional experiments can be carried out to verify the mechanisms of these genes in regulating tumorigenesis.
... Titin is a giant myofilament that extends from the Z-disk (N-terminus) to the M-band (C-terminus) region of the sarcomere and is now recognized as a major human disease gene. Many titin mutations are linked to cardiomyopathies and neuromuscular diseases [28]. ...
... Gene is widely expressed in cardiac and skeletal muscles, and mutations in FLNC were associated with skeletal myopathy, as well as hypertrophic, restrictive, and dilated cardiomyopathy [29]. The heterogeneous autopsy findings correlate with the described clinical manifestations of the FLNC gene and also show that arrhythmic complications may precede the development of clear structural changes in the heart muscle [25][26][27][28]. In this study, one family with a P/LP variant in FLNC gene, requested to be included in an assisted reproduction and preimplantation diagnosis program for primary prevention of the disease in offspring [30][31][32][33]. ...
Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00414-023-03007-z.
... The ratio of titin to type 1 collagen can be considered a prospective approach to assessing the severity of fibrosis. Titin is a protein maintaining sarcomere integrity by modeling passive tension, changing its conformation, isoform balance, as well as interacting with other myofilament components [6]. Physiological role of collagen is to provide mechanical power of myocardial matrix as well as the ability to transmit force generated by cardiomyocytes. ...
Intermittent hypoxia has been studied for many years as a promising non-pharmacological method of cardiovascular disease prevention. Hypoxic effects are accompanied by structural and functional changes in the myocardium. There is a direct link between the duration of hypoxic exposures and the severity of left ventricular myocardial remodeling. A range of histochemical markers of myocardial remodeling (cardiotrophin-1, titin, collagen type 1, annexin V) characterizing parenchymal-stromal relationships in the myocardium has shown high informativeness and prognostic value. The aim of the study was to examine cardiotrophin-1, titin, collagen type 1, annexin V and the morphofunctional state of the left ventricle of the heart in experimental rats exposed to intermittent 15-day (IH15) and 60-day hypoxia (IH60). Materials and methods. Intermittent hypoxia was modeled using 30 normotensive male Wistar rats, 7–8 months old, which were randomly assigned to 3 experimental groups of 10 animals each: 1) INT – a control group – intact animals (196.3 ± 6.8 g); 2) IH15 – 15-day hypoxia (205.6 ± 4.1 g); 3) IH60 – 60-day hypoxia (201.1 ± 5.5 g). The study compared the effects of intermittent hypoxia of varying duration: 15-day and 60-day hypoxia. Experimental modeling of intermittent hypoxia of 2 terms revealed a number of differences between the effects dependent on this factor duration through functional (blood pressure measurement, echocardiography) and immunofluorescent studies. Results. Blood pressure in rats of both groups was in the normotensive range, but an increase in systolic by 10 % and diastolic by 19 % was found in IH60 group compared to IH15 group (p < 0.05). In IH15 group, there was a significant decrease in end-diastolic dimension by 20 %, end-systolic dimension by 22 %, an increase in the thickness of left ventricular posterior wall by 44 % and interventricular septum by 33 % as well as left ventricular mass by 12 %, indicating concentric remodeling of the left ventricle, the development of which was confirmed by a 76 % increase in relative wall thickness compared to that in the control group (p < 0.05). Along with these changes, a decrease in end-diastolic volume by 47 %, end-systolic volume by 48 %, stroke volume by 49 % and cardiac output by 50 % with preserved ejection fraction was revealed (p < 0.05). While the parameters of IH60 rats were characterized by an increase in the thickness of interventricular septum by 33 % and left ventricular posterior wall by 17 %, as well as left ventricle mass by 23 %, relative left ventricular wall thickness was 15 % higher than the control value (p < 0.05). At the same time, diastolic volume was 9 % decreased and systolic volume was 24 % increased (p < 0.05). Also, cardiac output was increased by 58 % compared to that in 15-day hypoxic rats with an 8 % decrease in ejection fraction (p < 0.05). The concentrations of markers in IH60 group exceeded those in IH15, namely: cardiotrophin-1 by 39 %, titin by 70 %, collagen type 1 by 60 % and annexin V by 130 % (p < 0.05). Conclusions. 15-day hypoxia forms concentric left ventricular hypertrophy according to echocardiography findings; the study of marker profile of myocardial remodeling has revealed the development of moderate hypertrophy with increased resilient-elastic properties and decreased intensity of cardiomyocyte death. Remodeling caused by 60-day hypoxia is characterized by the eccentric pattern of changes with severe hypertrophy, significant fibrosis associated with apoptosis of cardiomyocytes. Such morphofunctional state of the myocardium may indicate the initial stages of maladaptation, increasing the risk of heart failure development.
... The most recent published version of our model incorporated titin stiffness as a variable but did not account for thin filament regulation, which we had in the previous version (Williams et al., 2013). Titin has a critical role in myocyte elasticity, stretch-dependent activation, and intracellular mechanosensing, and its variants are the leading cause of genetic DCM (Kellermayer et al., 2019). In this study, we incorporate both thin filament regulation and account for titin stiffness. ...
The timing and magnitude of force generation by a muscle depend on complex interactions in a compliant, contractile filament lattice. Perturbations in these interactions can result in cardiac muscle diseases. In this study, we address the fundamental challenge of connecting the temporal features of cardiac twitches to underlying rate constants and their perturbations associated with genetic cardiomyopathies. Current state-of-the-art metrics for characterizing the mechanical consequence of cardiac muscle disease do not utilize information embedded in the complete time course of twitch force. We pair dimension reduction techniques and machine learning methods to classify underlying perturbations that shape the timing of twitch force. To do this, we created a large twitch dataset using a spatially explicit Monte Carlo model of muscle contraction. Uniquely, we modified the rate constants of this model in line with mouse models of cardiac muscle disease and varied mutation penetrance. Ultimately, the results of this study show that machine learning models combined with biologically informed dimension reduction techniques can yield excellent classification accuracy of underlying muscle perturbations.
... The other precious prognostic biomarkers are autoantibodies against titin and ryanodine receptor (RyR). Titin is a huge abundant filamentous protein located in the striated muscles which is one of the sarcomere proteins and RyR is a calcium (Ca 2+ ) channel located in the sarcoplasmic reticulum membrane which plays a role in Ca 2+ release from the sarcolemma to the cytoplasm to launch excitation-contraction coupling [23,24]. Among the AChR+ MG patients, 20-40% of them also have a positive test for titin antibodies. ...
Myasthenia gravis (MG) is a rare auto-immune neuromuscular junction (NMJ) disorder which is caused by formation of autoantibodies and destruction of NMJ components. The MG diagnosis is based on the symptoms, autoantibodies detection and paraclinical tests. Given that MG patients have so many differential diagnosis and various medication responses, choosing an accurate diagnosis and the therapy plan in MG is challenging. According to the studies, there are the immunologic, genetic, microRNAs, gut microbiome, and other established or newly proposed biomarkers for diagnosis and prognosis of MG. More studies are needed to provide better collection of biomarkers in MG patients and evaluate their role in MG pathology.
