Affinage

TTN

Titin · UniProt Q8WZ42

Length
34350 aa
Mass
3816.0 kDa
Annotated
2026-06-10
100 papers in source corpus 15 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Titin (TTN) is a giant sarcomeric protein whose intrinsically disordered repeat segments provide myofibrillar elasticity and whose distinct structural domains anchor the contractile apparatus from the Z-disc/I-band transition through the A-band to the M-line, with model-organism work demonstrating direct actin and myosin binding by multiple titin segments and circular-dichroism evidence that its PEVK-like repeats are intrinsically disordered, consistent with an elastic, scaffolding role (PMID:20346955). Heterozygous truncating TTN variants are a major cause of dilated cardiomyopathy (DCM), acting through two convergent mechanisms: haploinsufficiency, the direct reduction of full-length titin shown in patient hearts and recapitulated by Ttn knockdown in mice, and the production of toxic truncated peptides that form intracellular aggregates with deregulated ubiquitin-dependent quality control (PMID:34731013, PMID:31705051). The A-band/I-band axis governs pathogenicity: A-band truncations generate peptides that integrate into nascent myofibrils and impair myofibrillogenesis more severely than I-band truncations, and CRISPR reading-frame repair or promoter-targeted CRISPR activation restores full-length titin and rescues sarcomere assembly and contractile force (PMID:34905694, PMID:38235591). At the M-line, mutations in the terminal exons cause tibial muscular dystrophy and, in a gene-dosage manner, the more severe LGMD2J, and loss of the M-line titin kinase domain produces severe cardiac morphogenesis defects (PMID:12145747, PMID:15728284, PMID:24105469). Recessive truncating and strongly destabilizing missense variants affecting Ig/FN3 domain folding cause congenital myopathies, where loss of full-length titin and increased titin degradation are the shared molecular consequence (PMID:23975875, PMID:33449170). The TTN locus is heavily alternatively spliced, regulated in part by RBM20 and including metatranscript-only and Novex exons with developmental expression, such that splice-disrupting variants cause myopathy and arthrogryposis whose severity tracks fetal-specific exon usage (PMID:29438341, PMID:31660661, PMID:34461741).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 High

    Established that titin defects directly cause inherited muscle disease by linking truncating and missense TTN variants to dilated cardiomyopathy and to M-line-restricted tibial muscular dystrophy.

    Evidence Genetic linkage with epitope-specific anti-titin western blot showing truncated/cleaved protein in DCM, and cosegregation with exon-specific immunohistochemistry showing loss of C-terminal epitopes in TMD muscle

    PMID:11788824 PMID:12145747

    Open questions at the time
    • Did not resolve whether DCM arises from loss of full-length protein or toxic truncated fragments
    • Functional consequence of the missense Ig-fold disruption not biochemically dissected
  2. 2005 Medium

    Demonstrated a gene-dosage relationship at the TTN M-line, where the same founder mutation produces mild TMD in heterozygotes and severe LGMD2J in homozygotes.

    Evidence Genotyping of 386 individuals with heterozygous vs. homozygous phenotype-genotype correlation

    PMID:15728284

    Open questions at the time
    • Molecular basis of the dosage threshold not defined
    • Single cohort
  3. 2010 Medium

    Provided biophysical and biochemical grounding for titin's elastic and scaffolding function by mapping actin/myosin-binding segments and showing repeat elements are intrinsically disordered.

    Evidence In vitro actin/myosin binding assays, circular dichroism, and molecular dynamics on C. elegans TTN-1 segments

    PMID:20346955

    Open questions at the time
    • Performed on an invertebrate ortholog rather than human titin
    • Single lab
  4. 2013 High

    Extended the disease spectrum to recessive myopathies and implicated the titin kinase domain, showing that loss of full-length titin and absent kinase function underlie centronuclear and core myopathies with cardiac involvement.

    Evidence Exome/genome sequencing with splicing assays and gel electrophoresis of patient muscle, plus in vitro titin kinase domain functional assays

    PMID:23975875 PMID:24105469

    Open questions at the time
    • Mechanism connecting kinase loss to cardiac morphogenesis not defined
    • Kinase substrate(s) not identified
  5. 2017 Medium

    Identified reduced passive myofibril stiffness as a contractile-phenotype feature of DCM hearts that was shared across mutation types and, in this sample, not attributable to detectable haploinsufficiency.

    Evidence In vitro passive stiffness and contractility measurements on isolated cardiac myofibrils from human DCM hearts

    PMID:29093449

    Open questions at the time
    • Only n=3 TTNtv samples
    • Failure to detect haploinsufficiency conflicts with later larger cohorts
  6. 2018 Medium

    Defined the regulatory architecture of TTN splicing, distinguishing RBM20-dependent splicing from RBM20-independent Novex isoform regulation and linking Novex expression to human cardiomyopathy.

    Evidence Cross-species RT-PCR, Rbm20 knockout rat hearts, and RT-PCR of Novex isoforms in human DCM/ARVC

    PMID:29438341

    Open questions at the time
    • Functional role of individual Novex isoforms in the sarcomere not established
    • Single lab
  7. 2019 High

    Connected developmental TTN splicing to disease and modeled haploinsufficiency in vivo, showing fetal-specific metatranscript exon usage explains age-improving phenotypes and that reduced cardiac Ttn alone produces DCM.

    Evidence Patient muscle splicing assays with fetal/adult RNA-seq for arthrogryposis, and AAV-shRNA Ttn knockdown mouse with echocardiography and rescue

    PMID:31660661 PMID:31705051

    Open questions at the time
    • Mouse knockdown does not separate haploinsufficiency from possible truncated-peptide effects of human variants
    • Yy1 rescue mechanism on titin protein not directly shown
  8. 2021 High

    Resolved the dual pathomechanism of TTNtv DCM, demonstrating both reduced full-length titin and toxic aggregation-prone truncated peptides, and proving causality through CRISPR correction and CRISPR activation that restored titin and contractile function.

    Evidence Western blot of 113 DCM/donor hearts, hiPSC-CM and engineered heart muscle with patient-derived and CRISPR-generated TTNtv, CRISPR-Cas9 reading-frame repair, dCas9-VPR promoter activation, and proteasome inhibition

    PMID:34731013 PMID:34905694 PMID:38235591

    Open questions at the time
    • Relative contribution of haploinsufficiency vs. toxic peptide may vary by variant position and model
    • Identity and regulation of the ubiquitin-quality-control machinery acting on truncated titin not defined
  9. 2021 High

    Defined the A-band/I-band positional axis of TTNtv pathogenicity and the biophysical basis of recessive missense disease, showing A-band peptides disrupt myofibrillogenesis and that domain-destabilizing missense variants phenocopy truncations.

    Evidence hiPSC-CM A-band vs I-band TTNtv with protein gels and 3D microtissue contractility, plus biophysical Ig/FN3 domain stability assays with clinical correlation

    PMID:33449170 PMID:34905694

    Open questions at the time
    • Structural detail of how truncated peptides incorporate into nascent myofibrils not resolved
    • Threshold of destabilization required for pathogenicity not quantified
  10. 2021 Medium

    Linked titin insufficiency to a regenerative signaling axis, showing Ttn reduction triggers partial cardiomyocyte cell-cycle re-entry that Yy1 can complete to suppress DCM.

    Evidence AAV-shRNA Ttn knockdown mice with EdU incorporation, Ccnd1/Ccnd2 profiling, and Yy1 overexpression rescue

    PMID:31705051

    Open questions at the time
    • Mechanism by which titin level controls cyclin D expression unknown
    • Translation to human cardiomyocytes not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How truncated titin peptides are recognized and routed by ubiquitin-dependent quality control, and the molecular substrate/signaling role of the titin kinase domain in cardiac morphogenesis, remain unresolved.
  • No E3 ligase or degradation pathway component for truncated titin identified in the corpus
  • No identified titin kinase substrate
  • Mechanism coupling titin level to cardiomyocyte cell-cycle genes undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 1 GO:0016740 transferase activity 1
Localization
GO:0005856 cytoskeleton 3
Pathway
R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-397014 Muscle contraction 2
Partners
CAPN3RBM20YY1
Complex memberships
sarcomere

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Heterozygous TTN mutations cause familial dilated cardiomyopathy (DCM). A 2-bp insertion in TTN exon 326 causes a frameshift truncating A-band titin; the truncated ~2 MDa protein expressed in skeletal muscle is further cleaved to a 1.14 MDa subfragment by site-specific proteolysis. A missense mutation (Trp930Arg) disrupts a conserved hydrophobic core of an immunoglobulin fold in the Z-disc–I-band transition zone. Genetic linkage, mutation identification, western blot with epitope-specific anti-titin antibodies demonstrating truncated protein and site-specific cleavage Nature genetics High 11788824
2002 Mutations in the last exon of TTN (Mex6) cause tibial muscular dystrophy (TMD). An 11-bp deletion/insertion in Mex6 and a Leu→Pro missense in Mex6 (adjacent to the calpain-3 binding site Mex5) lead to specific loss of carboxy-terminal titin epitopes in patient muscle, implicating M-line titin functional defect in disease pathogenesis. Genetic cosegregation analysis, immunohistochemistry with exon-specific antibodies showing loss of C-terminal titin epitopes in patient muscle biopsies American journal of human genetics High 12145747
2005 The same C-terminal M-line TTN Finnish founder mutation (FINmaj) in heterozygosity causes classic tibial muscular dystrophy (TMD), while homozygosity causes the more severe LGMD2J phenotype, establishing a gene-dosage effect at the TTN M-line locus. Genotyping of 386 individuals; phenotype–genotype correlation in heterozygous vs. homozygous carriers Neurology Medium 15728284
2010 C. elegans TTN-1 (titin ortholog) localizes to the I-band/outer A-band of obliquely striated sarcomeres; six distinct 300-residue segments interact with actin and/or myosin in vitro. Five classes of repetitive sequence elements (PEVT, CEEEI, AAPLE, DispRep, BLUE) are intrinsically disordered in aqueous solution, analogous to vertebrate titin PEVK segments, supporting an elasticity function. Western blot (~2 MDa band), immunofluorescence localization, in vitro actin/myosin binding assays, circular dichroism spectroscopy, molecular dynamics simulations Journal of molecular biology Medium 20346955
2013 Autosomal recessive compound heterozygous truncating TTN mutations cause centronuclear myopathy. Biochemical analyses of patient muscle demonstrated increased titin degradation and expression of truncated titin proteins, establishing that loss of full-length titin protein is a direct molecular consequence of these mutations. Whole-exome/genome sequencing, immunofluorescence on muscle biopsies, splicing assays, gel electrophoresis of patient muscle proteins Neurology High 23975875
2013 Recessive TTN truncating mutations (five in the M-line region) cause core myopathies with associated heart disease. In vitro functional studies documented the first reported absence of a functional titin kinase domain in humans, caused by an M-line TTN mutation, leading to a severe antenatal phenotype; this implicates the titin kinase domain in cardiac morphogenesis. TTN M-line-targeted sequencing, whole-exome sequencing, in vitro functional studies of titin kinase domain activity Human molecular genetics Medium 24105469
2017 In DCM human hearts with TTN truncating variants (TTNtv), myofibril passive stiffness is reduced ~38% compared to donor controls, but maximum contractile force and the N2BA/N2B titin isoform ratio are unchanged and titin haploinsufficiency is not detected, suggesting passive stiffness reduction is a shared DCM mechanism independent of truncation versus contractile protein mutation. Isolation of cardiac myofibrils from human DCM hearts (TTNtv and contractile protein mutation patients vs. donor controls); contractility and passive stiffness measurements in vitro Scientific reports Medium 29093449
2018 RBM20 regulates alternative splicing of TTN (a major RBM20 splicing target). Novex variant exons (45, 46, 48) of TTN are alternatively spliced in a species-specific manner; RBM20 knockout in rat hearts does not affect splicing of Novex variants, indicating Novex isoform splicing is RBM20-independent. Novex 2 and 3 expression levels are altered in human DCM/ARVC hearts. Cross-species RT-PCR and sequencing; Rbm20 knockout rat hearts; RT-PCR validation of Novex isoform expression in human cardiomyopathy Genes Medium 29438341
2019 A recurrent TTN intron 213 splice variant (c.39974-11T>G), inherited in trans with a second pathogenic TTN variant, causes arthrogryposis multiplex congenita and myopathy. Muscle RNA studies confirmed mis-splicing (in-frame exon 214 skipping or cryptic 3' splice-site use leading to frameshift). Fetal muscle RNA-seq showed predominant inclusion of exons 213–217 in TTN metatranscript-only isoforms, explaining the developmental phenotype and improvement with age. Muscle-derived RNA studies confirming mis-splicing; RNA-sequencing of 365 adult and 5 fetal muscle samples for exon inclusion quantification Human mutation High 31660661
2019 Titin haploinsufficiency caused by reduced cardiac Ttn expression (via AAV-mediated shRNA in mice) produces DCM with impaired cardiac performance, enlarged LV, and reduced LV wall thickness. Upregulation of Yin Yang 1 (Yy1) suppresses this DCM by modulating cell-growth-related genes and promoting cardiomyocyte cell cycle re-entry via Ccnd1/Ccnd2 upregulation. AAV-mediated shRNA Ttn knockdown mouse model; echocardiography; RNAseq gene profiling; EdU incorporation; overexpression rescue experiments Scientific reports Medium 31705051
2021 TTN truncating variants (TTNtv) cause DCM primarily via two mechanisms: (1) haploinsufficiency—direct demonstration of reduced full-length titin protein in TTNtv-DCM patient hearts with no compensatory increase in Cronos isoform; (2) toxic truncated titin proteins—present in 21/22 TTNtv-DCM hearts, forming intracellular aggregates with deregulated ubiquitin-dependent protein quality control rather than integrating into sarcomeres. In hiPSC-CM models, A-band TTNtv truncation peptides impair myofibrillogenesis. CRISPR correction of TTNtv eliminated truncated protein and raised wild-type titin, restoring contractility; proteasome inhibition increasing wild-type titin also improved function. Western blot of 113 DCM and donor heart tissues; hiPSC-CM models with patient-derived and CRISPR-generated TTNtv; engineered heart muscle contractility assays; CRISPR-Cas9 correction; proteasome inhibition Science translational medicine High 34731013
2021 A-band TTNtv dose-dependently impairs cardiac microtissue twitch force and reduces full-length TTN levels more severely than I-band TTNtv. A-band TTNtv produces abundant truncated TTN peptides that integrate into nascent myofibril-like structures and impair myofibrillogenesis—a mechanism not shared by I-band TTNtv. CRISPR reading-frame repair of the A-band TTNtv restored full-length TTN protein, reduced truncation peptides, and rescued sarcomere function. hiPSC-CM models with A-band and I-band TTNtv; TTN protein gel electrophoresis; immunofluorescence; 3D cardiac microtissue contractility assays; CRISPR-Cas9 reading frame repair; next-generation sequencing Circulation High 34905694
2021 Noncanonical splice-altering variants in TTN splice regions (especially at donor +5 and acceptor −3 positions) disrupt splicing as confirmed by in vitro splice assay and explain ~1–2% of DCM cases, providing a 10–20% increase in diagnostic yield. SpliceAI showed high positive predictive value (86–95%) but poor sensitivity (15–50%) for detecting these variants. In vitro splice assay of rare TTN splice region variants from 203 DCM cases and 3329 controls; bioinformatic analysis with SpliceAI Circulation. Genomic and precision medicine Medium 34461741
2021 Missense TTN mutations associated with congenital myopathies are strongly destabilizing to the Ig/FN3 domain fold. Biophysical analyses showed that destabilizing missense variants phenocopy truncating variants and are pathogenic when expressed on a truncating background (compound heterozygosity) or in homozygosity, but not in heterozygosity alone. Biophysical stability assays of expressed TTN domains bearing missense mutations; clinical correlation in 30 patients with compound heterozygous or homozygous TTN variants Acta neuropathologica Medium 33449170
2021 CRISPR activation targeting the TTN promoter or distal regulatory elements in 3D chromatin proximity rescued TTN protein deficits in TTNtv hiPSC-CMs, normalized sarcomere content and contractile function, and increased myofibril assembly-related transcripts—providing direct evidence that haploinsufficiency (rather than solely toxic truncated peptide) is a relevant pathomechanism of TTNtv DCM. dCas9-VPR CRISPR activation with guide RNAs targeting TTN promoter/regulatory elements; TTN protein gel electrophoresis; RNA sequencing; cardiac microtissue contractility assays; epigenetic/chromatin assays Circulation High 38235591
2021 Reduction of cardiac Ttn by shRNA in mice activates cardiomyocyte cell cycle re-entry by upregulating Ccnd1 and Ccnd2, but cardiomyocytes do not advance to S phase (no DNA replication by EdU incorporation). Yy1 overexpression further enhances Ccnd1/Ccnd2 and promotes DNA replication, suppressing DCM caused by Ttn insufficiency. AAV shRNA Ttn knockdown mouse; EdU incorporation assay; qPCR/RNAseq for Ccnd1/Ccnd2; Yy1 overexpression rescue Scientific reports Medium 31705051

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature genetics 453 11788824
2002 Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. American journal of human genetics 331 12145747
2014 A rising titan: TTN review and mutation update. Human mutation 193 24980681
2013 Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology 166 23975875
2011 Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. The journal of pain 149 22074755
2013 Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Human molecular genetics 144 24105469
2017 Functional Role of a Novel Long Noncoding RNA TTN-AS1 in Esophageal Squamous Cell Carcinoma Progression and Metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research 122 29101304
2019 LncRNA TTN-AS1 regulates osteosarcoma cell apoptosis and drug resistance via the miR-134-5p/MBTD1 axis. Aging 112 31600142
2022 Titin (TTN): from molecule to modifications, mechanics, and medical significance. Cardiovascular research 110 34662387
2019 The Giant Protein Titin's Role in Cardiomyopathy: Genetic, Transcriptional, and Post-translational Modifications of TTN and Their Contribution to Cardiac Disease. Frontiers in physiology 110 31849696
2021 Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations. Science translational medicine 101 34731013
2019 LncRNA TTN-AS1 promotes migration, invasion, and epithelial mesenchymal transition of lung adenocarcinoma via sponging miR-142-5p to regulate CDK5. Cell death & disease 97 31363080
2020 Spontaneous mutations in the single TTN gene represent high tumor mutation burden. NPJ genomic medicine 91 32821429
2005 Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 85 15728284
2019 Circular RNA TTN Acts As a miR-432 Sponge to Facilitate Proliferation and Differentiation of Myoblasts via the IGF2/PI3K/AKT Signaling Pathway. Molecular therapy. Nucleic acids 83 31770673
2009 Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis. British journal of haematology 80 19594743
2016 HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo- and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 77 27903463
2013 Genetic variants associated with development of TMD and its intermediate phenotypes: the genetic architecture of TMD in the OPPERA prospective cohort study. The journal of pain 75 24275226
2018 Long non-coding RNA TTN-AS1 promotes cell growth and metastasis in cervical cancer via miR-573/E2F3. Biochemical and biophysical research communications 59 30135013
2019 LncRNA TTN-AS1 sponges miR-376a-3p to promote colorectal cancer progression via upregulating KLF15. Life sciences 55 31610194
1998 Expression of genes (CAPN3, SGCA, SGCB, and TTN) involved in progressive muscular dystrophies during early human development. Genomics 55 9521867
2021 Making sense of missense variants in TTN-related congenital myopathies. Acta neuropathologica 53 33449170
2019 Long non-coding RNA TTN-AS1 facilitates tumorigenesis of papillary thyroid cancer through modulating the miR-153-3p/ZNRF2 axis. The journal of gene medicine 50 30811764
2019 LINC00680 and TTN-AS1 Stabilized by EIF4A3 Promoted Malignant Biological Behaviors of Glioblastoma Cells. Molecular therapy. Nucleic acids 47 32000032
2021 Effect of TTN Mutations on Immune Microenvironment and Efficacy of Immunotherapy in Lung Adenocarcinoma Patients. Frontiers in oncology 46 34513703
2019 LncRNA TTN-AS1 drives invasion and migration of lung adenocarcinoma cells via modulation of miR-4677-3p/ZEB1 axis. Journal of cellular biochemistry 43 31173403
2017 Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. Scientific reports 43 29093449
2016 Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy. Molecular neurobiology 41 27796757
2020 LncRNA TTN-AS1 promotes the progression of cholangiocarcinoma via the miR-320a/neuropilin-1 axis. Cell death & disease 40 32801339
2020 Long noncoding RNA TTN-AS1 facilitates tumorigenesis and metastasis by maintaining TTN expression in skin cutaneous melanoma. Cell death & disease 38 32820147
2021 Reading Frame Repair of TTN Truncation Variants Restores Titin Quantity and Functions. Circulation 36 34905694
2019 Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. Human mutation 35 31660661
2016 Estrogen-Induced Monocytic Response Correlates with TMD Pain: A Case Control Study. Journal of dental research 35 27856968
2007 Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome. British journal of haematology 35 17456055
2020 LncRNA TTN-AS1 acts as sponge for miR-15b-5p to regulate FBXW7 expression in ovarian cancer. BioFactors (Oxford, England) 33 32049388
2020 LncRNA TTN-AS1 promotes the progression of oral squamous cell carcinoma via miR-411-3p/NFAT5 axis. Cancer cell international 32 32863773
2019 LncRNA TTN-AS1 contributes to gastric cancer progression by acting as a competing endogenous RNA of miR-376b-3p. Neoplasma 32 30943745
2020 lncRNA TTN-AS1 facilitates proliferation, invasion, and epithelial-mesenchymal transition of breast cancer cells by regulating miR-139-5p/ZEB1 axis. Journal of cellular biochemistry 28 32100921
2020 LncRNA TTN-AS1 intensifies sorafenib resistance in hepatocellular carcinoma by sponging miR-16-5p and upregulation of cyclin E1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 28 33378944
2019 Long Non-Coding RNA TTN-AS1 Promotes the Proliferation and Invasion of Colorectal Cancer Cells by Activating miR-497-Mediated PI3K/Akt/mTOR Signaling. OncoTargets and therapy 28 31920341
2023 Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation. Genetics in medicine : official journal of the American College of Medical Genetics 27 36637017
2021 The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy. Genes 25 34201072
2021 TTN/TP53 mutation might act as the predictor for chemotherapy response in lung adenocarcinoma and lung squamous carcinoma patients. Translational cancer research 25 35116455
2019 Long non-coding RNA TTN-AS1 promotes the progression of lung adenocarcinoma by regulating PTEN/PI3K/AKT signaling pathway. Biochemical and biophysical research communications 25 31027732
2024 Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies. Scientific reports 23 38438525
2021 Long non-coding RNA TTN antisense RNA 1 facilitates hepatocellular carcinoma progression via regulating miR-139-5p/SPOCK1 axis. Bioengineered 23 33517826
2024 CRISPR Activation Reverses Haploinsufficiency and Functional Deficits Caused by TTN Truncation Variants. Circulation 22 38235591
2021 Contribution of Noncanonical Splice Variants to TTN Truncating Variant Cardiomyopathy. Circulation. Genomic and precision medicine 22 34461741
2019 Long non-coding RNA TTN-AS1 promotes cell proliferation and inhibits cell apoptosis in prostatic cancer by sponging miR-193a-5p. European review for medical and pharmacological sciences 22 31599406
2014 Severity of TMD related to age, sex and electromyographic analysis. Brazilian dental journal 22 24789293
2017 A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population. European journal of human genetics : EJHG 21 28295036
2017 A 'second truncation' in TTN causes early onset recessive muscular dystrophy. Neuromuscular disorders : NMD 21 28716623
2010 Extensive and modular intrinsically disordered segments in C. elegans TTN-1 and implications in filament binding, elasticity and oblique striation. Journal of molecular biology 20 20346955
2020 LncRNA TTN-AS1 Regulates miR-524-5p and RRM2 to Promote Breast Cancer Progression. OncoTargets and therapy 19 32547107
2020 lncRNA TTN‑AS1 upregulates RUNX1 to enhance glioma progression via sponging miR‑27b‑3p. Oncology reports 19 32705233
2022 SQLE facilitates the pancreatic cancer progression via the lncRNA-TTN-AS1/miR-133b/SQLE axis. Journal of cellular and molecular medicine 18 35638462
2021 Protective Role of lncRNA TTN-AS1 in Sepsis-Induced Myocardial Injury Via miR-29a/E2F2 Axis. Cardiovascular drugs and therapy 18 34519914
2020 LncRNA TTN-AS1 Promotes Progression of Non-Small Cell Lung Cancer via Regulating miR-491-5p/ZNF503 Axis. OncoTargets and therapy 18 32669856
2020 LncRNA TTN-AS1/miR-134-5p/PAK3 axis regulates the radiosensitivity of human large intestine cancer cells through the P21 pathway and AKT/GSK-3β/β-catenin pathway. Cell biology international 18 32749739
2020 LncRNA TTN‑AS1 promotes endometrial cancer by sponging miR‑376a‑3p. Oncology reports 18 32945477
2021 Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy. Frontiers in cardiovascular medicine 17 33996946
2020 RETRACTED: Long non-coding RNA TTN-AS1 promotes tumorigenesis of ovarian cancer through modulating the miR-139-5p/ROCK2 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 32006899
2020 Assessment of PDK4 and TTN gene variants in 48 Doberman Pinschers with dilated cardiomyopathy. Journal of the American Veterinary Medical Association 17 33135971
2022 TTN-AS1 delivered by gastric cancer cell-derived exosome induces gastric cancer progression through in vivo and in vitro studies. Cell biology and toxicology 16 36214926
2021 Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia. International journal of biological macromolecules 16 34838574
2019 Novel TTN mutations and muscle imaging characteristics in congenital titinopathy. Annals of clinical and translational neurology 16 31353864
2019 Long noncoding RNA TTN-AS1 enhances the malignant characteristics of osteosarcoma by acting as a competing endogenous RNA on microRNA-376a thereby upregulating dickkopf-1. Aging 16 31525734
2019 Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10. BMC medical genetics 16 31664938
2017 TTN genotype is associated with fascicle length and marathon running performance. Scandinavian journal of medicine & science in sports 16 28581678
2021 Polymorphisms in the HTR2A and HTR3A Genes Contribute to Pain in TMD Myalgia. Frontiers in oral health 15 35047998
2020 COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial. Journal of dental research 15 33030089
2020 Long non‑coding RNA TTN‑AS1 regulates the proliferation, invasion and migration of triple‑negative breast cancer by targeting miR‑211‑5p. Molecular medicine reports 15 33179096
2008 Bacterial diversity in synovial fluids of patients with TMD determined by cloning and sequencing analysis of the 16S ribosomal RNA gene. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 15 18206402
2024 Spatially Confined Microcells: A Path toward TMD Catalyst Design. Chemical reviews 14 38748433
2019 Low mutation rate in the TTN gene in paediatric patients with dilated cardiomyopathy - a pilot study. Scientific reports 14 31712709
2018 Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations. Molecular medicine reports 14 29568937
2016 Whole-Exome Sequencing Identifies Two Novel TTN Mutations in Chinese Families with Dilated Cardiomyopathy. Cardiology 14 27544385
2024 Circulating tumor cell-derived exosome-transmitted long non-coding RNA TTN-AS1 can promote the proliferation and migration of cholangiocarcinoma cells. Journal of nanobiotechnology 13 38637832
2025 Analysis of TTN Truncating Variants in >74 000 Cases Reveals New Clinically Relevant Gene Regions. Circulation. Genomic and precision medicine 12 39968638
2022 LncRNA TTN-AS1 confers tamoxifen resistance in breast cancer via sponging miR-107 to modulate PI3K/AKT signaling pathway. American journal of translational research 12 35559394
2021 Intranuclear Delivery of HIF-1α-TMD Alleviates EAE via Functional Conversion of TH17 Cells. Frontiers in immunology 12 34745114
2023 Association of oral behaviours and psychological factors with selected genotypes in pain-related TMD. Oral diseases 11 37036392
2017 Germline TTN variants are enriched in PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome. NPJ genomic medicine 11 29263846
2022 Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes. Journal of personalized medicine 10 35207729
2021 A novel long non-coding RNA TTN-AS1/microRNA-589-5p/FOXP1 positive feedback loop increases the proliferation, migration and invasion of pancreatic cancer cell lines. Oncology letters 10 34584569
2019 Novel missense variant in TTN cosegregating with familial atrioventricular block. European journal of medical genetics 10 31470098
2019 Long noncoding RNA TTN-AS1 promotes the proliferation and migration of prostate cancer by inhibiting miR-1271 level. European review for medical and pharmacological sciences 10 31858535
2013 SNPs of MYPN and TTN genes are associated to meat and carcass traits in Italian Large White and Italian Duroc pigs. Molecular biology reports 10 24158610
2003 Transient tachypnea of the newborn (TTN): a role for polymorphisms of surfactant protein B (SP-B) encoding gene? Klinische Padiatrie 10 14520584
2024 Oxide and 2D TMD semiconductors for 3D DRAM cell transistors. Nanoscale horizons 9 38563255
2024 Clinical Characteristics and Outcomes in Patients With Atrial Fibrillation and Pathogenic TTN Variants. JACC. Clinical electrophysiology 9 39453294
2021 Clinical Considerations for a Family with Dilated Cardiomyopathy, Sudden Cardiac Death, and a Novel TTN Frameshift Mutation. International journal of molecular sciences 9 33445410
2019 A novel TTN deletion in a family with skeletal myopathy, facial weakness, and dilated cardiomyopathy. Molecular genetics & genomic medicine 9 31489791
2019 Upregulation of Yy1 Suppresses Dilated Cardiomyopathy caused by Ttn insufficiency. Scientific reports 9 31705051
2021 Implications of an Improved Model of the TSH Receptor Transmembrane Domain (TSHR-TMD-TRIO). Endocrinology 8 33693584
2021 Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family. Frontiers in neuroscience 8 33746696
2021 Silencing of the Long Non-Coding RNA TTN-AS1 Attenuates the Malignant Progression of Osteosarcoma Cells by Regulating the miR-16-1-3p/TFAP4 Axis. Frontiers in oncology 8 34141611
2020 Long Non-Coding RNA TTN-AS1 Serves as a Competing Endogenous RNA of miR-195 to Facilitate Clear Cell Renal Cell Carcinoma Progression. Cancer management and research 8 32440207
2018 Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing. Genes 8 29438341
2016 T/Tn immunotherapy avoiding immune deviation. International journal of immunopathology and pharmacology 8 27760846

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