observed that the mTORCI inhibitor rapamycin is able to rescue the attenuated autophagy in rat hearts containing TTNtv mutations [2]. Keywords: In a large DCM patient cohort, Roberts et al. MA, Quijano-Roy M13 primers were used to perform Sanger sequencing using an ABI PRISM 3130XL Genetic Analyzer (Applied Biosystems). This study was funded by National Institutes of Health grants R35HL144998, R01AR073179 and Interdisciplinary Training in Cardiovascular Research T32 HL007249. et al. [1] The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Titin-truncating variants affect heart function in disease cohorts and the general population. Next-generation sequencing is rapidly being implemented into routine clinical practice, improving the diagnostic rate for patients with neuromuscular diseases.21-23 Almost all NGS screenings reveal many rare and private titin variants and their clinical interpretation is particularly challenging.5,19,24-26 By using MotorPlex (Agilent Technologies), a targeted NGS panel, we screened TTN and the other muscle disease genes in 504 patients with skeletal muscle disorders.25,26 Here, we describe the approach used for the NGS data interpretation and we propose a workflow for a more straightforward and reproducible interpretation of the clinical meaning of titin variants. Identifying 2 truncating variants in trans results in a diagnosis of titinopathy, which may be corroborated by a WB showing the absence or a severe reduction of the C-terminal protein (patient IV or previously reported patients9,34). Clinically evaluating single heterozygous truncating variants is more complex (Figure 3). Western blotting analyses showed a reduced intensity of small C-terminal titin protein fragments and the presence of an additional band due to the splicing defect (Figure 1). Titin is a large (3-4 MDa) and abundant protein that forms the third myofilament type of striated muscle where it spans half the sarcomere, from the Z-disk to the M-line. Background and Objectives Duchenne muscular dystrophy (DMD) is a rare progressive disease that is often diagnosed in early childhood and leads to considerably reduced life expectancy; because of its rarity, research literature and patient numbers are limited. Clearly, more research is required into the pathomechanism by which TTNtv mutations induce DCM and into the possibility of exon skipping as a therapy. Many of the DCM-causing TTN mutations are heterozygous truncating variants (TTNtv) that include frameshift, nonsense, and essential splice site mutations and are over-represented in the A-band segment of titin [56,96], see Figure 1. Titin is evolutionarily old, and many regions are highly conserved. Main Outcomes and Measures J, Evil Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Why are there elusive variants in TTN? . [71], and UniProt (https://www.uniprot.org/uniprot/{"type":"entrez-protein","attrs":{"text":"Q8WZ42","term_id":"384872704","term_text":"Q8WZ42"}}Q8WZ42)[107]. Muscular dystrophy is a progressive condition that eventually leads to disability. In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in, The identification of novel mutations in the, Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Unauthorized use of these marks is strictly prohibited. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy with an incidence of 1 in 5000-9000 live born males per year. It has also been proposed that the upregulation of cronos titin[24], a novel titin isoform driven by an internal promoter (Figure 1), could rescue the effects of truncating mutations that localize proximal to its internal I-band promoter [123,24]. E, Monforte Schafer et. De Cid Therefore, alcohol is an additional environmental risk that can contribute to a more severe outcome of TTNtv-associated DCM. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Corresponding Author: Marco Savarese, PhD, Folkhlsan Research Center, Medicum, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland (marco.savarese@helsinki.fi). Truncations of titin causing dilated cardiomyopathy. No signs of cardiomyopathy were detected on heart ultrasonography. In addition, women carrying TTNtv mutations have a better prognosis than men [56,30]. Based on the metabolic changes in TTNtv+ humans and animal models, mTOR pathway modulation with metformin or rapalogues (rapamycin analogues) could serve as a potential treatment for TTNtv-induced DCM [110,2]. F, et al. [1] [2] This condition is less common and less severe than Duchenne muscular dystrophy (DMD). Correction: This article was corrected online August 8, 2018, to correct Ms Ruggieris degree. In a man in his early 30s with healthy parents and siblings (patient IV), we found a splice site variant (c.107377+1G>A in intron 362) on the maternal allele and a nonsense variant (p.Tyr21719* in exon 312) on the paternal allele. et al. Savarese Muscular dystrophy is a genetic health disease that affects the body's muscles. Am. Shes a child of Corey and Is, and we carry the gene. Duchenne muscular dystrophy (DMD) <10 per 100,000 in male <1 per million in female: 2 to 6 years : Muscle weakness and wasting affect pelvis, upper arms, and upper legs. The patient, as well as his similarly affected sibling, harbored a single-nucleotide duplication (p.Arg26562Thrfs*12) on the maternal allele. Due to alternative splicing, adult full-length cardiac isoforms differ in the length of their tandem and PEVK segments in the I-band and their stiffness varies accordingly [11,17,118] [32]. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. J. Hum. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Currently available bioinformatics tools37 combined with customized comparative genomic hybridization arrays28,38 should be used to assess the presence of large deletions or duplications39 in unsolved cases. The human titin gene contains 364 exons, of which 363 exons are coding exons. Similarly, others reported that TTNtv+ does not appear to be associated with worse prognosis and DCM patients with TTNtv are unaccompanied by conduction disease [30]. Next-generation sequencing for molecular diagnosis of neuromuscular diseases. Giugliano et al. Recently, TTNtv-induced DCM has also been associated with Z-disk, I-band and M-band exons in a small subset of patients [99]. In addition to providing elasticity, these segments also interact with signaling proteins and have been proposed to function as mechanosensor complexes [114,95,67,88,46,81,77] with mouse models that genetically target individual spring elements supporting such roles [93,48,61,94,23,15]. Savarese The 2 patients were siblings (mid-40s and mid-50s, respectively) and showed a slowly progressive distal myopathy with onset in the second decade. An evaluation of titin gene variants that combined genetic, clinical, and imaging data with messenger RNA and/or protein studies identified 9 patients with a titinopathy and 4 patients with possible titinopathy. Interestingly, mutated iPSC cardiomyocytes, derived from DCM patients with TTNtv, show attenuated response to isoproterenol, [Ca2+]out and angiotensin-ll. Krger Comparing TTNtv+ and TTNtv DCM patients, Roberts et al. Chauveau The mutated residue is shown as CPK. Copyright 2019 Elsevier B.V. All rights reserved. Alternative domain names based on TITINdb (http://fraternalilab.kcl.ac.uk/TITINdb/), see Laddach et al. V, Rispoli TEEN Mom star Leah Messer has shared many glimpses into her daughter Ali's brave battle with Muscular Dystrophy. The mutation to proline will induce steric restrictions most probably causing a reduced stability and a structural disruption. The interpretation of TTN missense variants may also benefit from the establishment of clinical and research consortia able to combine cohorts of patients into larger groups.43. Finally, Gramlich et al. Sequence variants in TTN are described according to the coding DNA reference sequence (LRG_391t1), covering transcript variant-IC (NM_001267550.1). Increasing evidence is indicating that titin truncating variants cause recessive skeletal muscle disorders.9,15,16,34 In the presence of monoallelic PTVs, we suggest performing a WB analysis that represents the most valuable and potentially conclusive test, as it is the only available tool able to predict the presence of further elusive truncating variants in trans (as seen in patient VIII and in a previously reported patient9). J, Vihola P, Marchand V. Limb-girdle muscular dystrophiesinternational collaborations for translational research. Due to its enormous size, TTN has been insufficiently analyzed in the past. 8600 Rockville Pike M, Ktter We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. C, Rowell the gene encoding the giant skeletal-muscle protein titin. A, Patient VIII with a single identified protein truncating variant shows a severe reduction of titin C-terminal fractions of all sizes; patient IV presents a reduced amount of the small (<20 kDa) titin fragments, and additionally the presence of a truncated fragment (arrowheads) resulting from the aberrant splicing due to the splice site mutation in intron 362. Methods: Molecular genetic analysis was performed for 52 patients (27 female and 25 male) from . 1,2 DMD is caused by mutations in the DMD gene located on the short arm of the X chromosome. D, Position of p.Trp33529Arg using the structure 2JBO. Others are more severe and start needing additional help between 10 and 20.. M. Next-generation sequencing approaches for the diagnosis of skeletal muscle disorders. Published Online: February 12, 2018. doi:10.1001/jamaneurol.2017.4899. MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples. P, Vihola O, Verellen This muscle helps control up-and-down movement of the foot. L, DAurizio Direct-zol RNA MiniPrep Kit (Zymo Research) was used to extract RNA from muscle biopsies. The IA zone is near the ends of the thick filaments and is striking in that the regular domain patterns of Ig and Fnlll domains is broken with a stretch of 6 Fnlll domains that is found preceding the D zone. Moreover, TTNtvs show a high penetrance after the age of 40 years and there is a possibility that secondary stressors are needed to develop DCM phenotype [56,27]. al developed 2 rat strains and modeled a proximal and distal TTNtv mutation and their RNA-seq study revealed a profound nonsense mediated mRNA decay (NMD) of the allele with TTNtv, indicating haploinsufficiency[99]. MC, Alfaro Ponce PubMedGoogle ScholarCrossref 3. The signs and symptoms of this condition typically appear after age 35. H, Somer Currently, there is much uncertainty about the exact mechanism by which titin truncating mutations lead to a cardiac phenotype. However, a complete molecular characterization of variants affecting the canonical or noncanonical splice sites by cDNA or protein studies is suggested. Nigro Patients with DMD, however, have a shorter life expectancy. F, Bethesda, MD 20894, Web Policies J, A segregation study confirmed that none of the 3 unaffected siblings were compound heterozygous for these TTN missense variants. Accepted for Publication: August 6, 2017. Overall, the importance of changes in cardiac metabolism and calcium handling in DCM caused by TTNtv warrant further investigation, including whether these changes develop directly from the truncating mutation or, more likely, are secondary effects. We thought that she had been tested, but I guess that was for some other research. Titin in muscular dystrophy and cardiomyopathy: Urinary . Risk of bias had little impact on pooled results. Titins N-terminus is embedded in the Z-disk and acts as a mechano-sensor [65]. Features of Titin-Related Skeletal Musical Disorders. Mutations in the titin (TTN) gene on chromosome 2q31 most often produce autosomal dominant tibial muscular dystrophy, a distal muscular dystrophy of mid-adult life with prominent involvement of the tibialis anterior and toe extensor muscles. Tasca T, Fanin Titin isoforms assembled from the metatranscript, cardiac N2BA, cardiac N2B, skeletal muscle N2A, Novex3 and Cronos transcripts (from top to bottom). Genet. These mutations cause either a dominant, mild, and late-onset distal leg phenotype, or recessive phenotypes.7-9,11 Muscle imaging is mandatory and often very informative (Table 2). Titin has a maximum molecular mass of ~4200 kDa[69,11] and has a modular domain composition consisting of immunoglobulin (Ig) and fibronectin type III (FnIII) domains and unique sequences [69,106] (see Figure 1 The former is located in an Fn3 domain in the A-band portion of titin, and in silico studies predicted that the amino acid is located on the external surface of the domain, possibly affecting the binding to the interactors. Indeed, 1-3% of the general population has a TTNtv, and it has been proposed that additional genetic and/or environmental stressors might be needed to unmask the effects of TTNtv [108,111,97,78,110,40]. In an extensive study of 504 mainly adult, patients who had not received a genetic diagnosis and were presenting with clinical signs of muscular dystrophy, congenital myopathy, or other skeletal muscle disorders, we identified 9 novel patients (1.8%) with titinopathy and 4 patients (0.8%) with very likely disease-causing TTN mutations. In this case series, 504 patients with skeletal muscle disorders were screened with a targeted resequencing approach. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. 2016 Aug 30;3(3):293-308. doi: 10.3233/JND-160158. doi:10.1001/jamaneurol.2017.4899. Hence, it has been suggested that TTNtv can be tolerated in the healthy population because the majority of the mutations fall in I-band exons that are subject to alternative splicing [96,60]. Patient VI was a woman in her mid-50s presenting in her early 30s with frequent tripping. Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Additionally, research groups are focusing on exon skipping approaches to cure TTNtv-associated DCM. In addition, 2 missense variants were identified on the paternal allele. Results showed that titin deficiency leads to sarcomere disassembly and atrophy in striated muscle and eventually DCM. R, Titins M-band region contains the serine/threonine kinase (TK) domain and is involved in numerous signaling pathways [83,116,115,91,90,39,19]. Multiple mechanisms have been proposed to explain TTNtv-induced DCM: haploinsufficiency, poison-peptide/dominant-negative mechanism, and perturbation of cardiac metabolism and signaling. S, S, Glumac We discuss the clinical significance of U-TN in the diagnosis of muscular dystrophies and differential diagnosis of cardiomyopathies, as well as risk stratification in dilated cardiomyopathy. NIHMS1525590-supplement-424_2019_2272_MOESM1_ESM.pdf. All the patients or their legal guardians provided written informed consent. In this case series, 504 patients with skeletal muscle disorders were screened with a targeted resequencing approach. The distal myopathies belong to a larger group of disorders known as the muscular dystrophies. People with centronuclear myopathy begin experiencing muscle weakness at any time from birth to early adulthood. She explained, I felt pretty confident that she didnt have it, so I wasnt too worried about it., According to Muscular Dystrophy Canada, Physical and occupational therapy, proper respiratory care, exercise, assistive devices, and orthopedic surgery may help to preserve muscle function and enhance quality of life.. Messenger RNA analyses confirmed the splicing effect of the intronic variant (eFigure in the Supplement). N, Bale Muscular dystrophy is a group of diseases that cause progressive weakness and loss of muscle mass. The C-zone region of titin likely plays a role in anchoring MyBP-C[31], regulating actomyosin interaction[82] and regulating the thick filament length[103]. 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Titin is a large (3-4 MDa) and abundant protein that forms the third myofilament type of striated muscle where it spans half the sarcomere, from the Z-disk to the M-line. et al. et al; ACMG Laboratory Quality Assurance Committee. He received a diagnosis of dilated cardiomyopathy without arrhythmias in his late teens. Savarese Echocardiography results in her early 50s showed mild left ventricular hypokinesia and a mildly reduced ejection fraction (43%). FOIA M, Marwah Life expectancy for muscular dystrophy depends on the type. National Library of Medicine Schafer Complementary DNA (cDNA) synthesis was performed using RevertAid H Minus Reverse Transcriptase (Thermo Scientific). Be sure to join our Teen Mom Facebook group to chat about all the latest updates and juicy gossip! No heart or respiratory involvement was observed. Yes, MD is a genetic disorder and can be inherited from ones parents. Written by Tavishi Dogra | Updated : April 14, 2023 8:54 AM IST. In this model a second genetic variant and/or environmental stressor is needed, as a second or third hit, to uncover the effects of the TTNtv. The muscular dystrophies (MDs) are a heterogeneous group of inherited disorders characterized by progressive weakness and degeneration of skeletal muscles ( Table ). Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy. et al. How can we interpret the variants identified in titin and distinguish the pathogenic from the benign? Savarese J, Le Gras Acquisition, analysis, or interpretation of data: All authors. Ceyhan-Birsoy A new titinopathy: childhood-juvenile onset Emery-Dreifusslike phenotype without cardiomyopathy. D, Witt & research is showing a life expectancy of around 70 years, as long as there are no signs of heart or lung failure. However, a mouse model in which titins IA junction was targeted revealed that deleting the IA junction does not alter thick filament length[44]. 2019 May; 471(5): 673682. Western Blot for C-Terminal Titin Fragments, Figure 3. Max was diagnosed 11 years ago at age 4; Rowen and Charlie were diagnosed in the months following at ages 2 years and 7 months. Domain composition of the metatranscript of titin and Novex-3 titin. R, Roudaut 90 Day Fiance's Paul and Karine Back on OnlyFans to 'Pay for Lawyer Fees', 90 Day Fiances Paul, Karine Officially Back Together: She Begged', Inside 1000-Lb. 2016;7:76. In particular, a c.18970A>C causing a substitution of a threonine with a proline at position 6324 was identified. The amino acid substitution may affect the interaction with ligands in this region (Figure 2B). Adv Clin Chem. H. Muscular dystrophy with separate clinical phenotypes in a large family. Understanding Titin Variants in the Age of Next-Generation Sequencing, Muscle Imaging, Histological Studies, and Western Blot Analysis, Patients With Previously Described Mutations, Patients With Biallelic Protein Truncating Variants, Patients With a Single Heterozygous Protein Truncating Variant, To register for email alerts, access free PDF, and more, Get unlimited access and a printable PDF ($40.00), 2023 American Medical Association. M, Udd Interestingly, recent whole-exome sequencing studies by Ahlberg et al. The https:// ensures that you are connecting to the G, Mutarelli Second, additional elusive mutations may be deep intronic or structural variants. Our study has limitations. 2002 Sep. 71(3):492-500. et al. She hasnt been tested. and transmitted securely. A, Sarparanta J, Vihola 219th ENMC International Workshop Titinopathies International database of titin mutations and phenotypes, Heemskerk, The Netherlands, 29 April-1 May 2016. Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies. 8600 Rockville Pike Evil Muscle imaging findings in GNE myopathy. Epub 2018 Jun 2. See text for details. Carmignac A specific workflow for the clinical interpretation of genetic findings in titin is suggested. Harris E, Tpf A, Vihola A, Evil A, Barresi R, Hudson J, Hackman P, Herron B, MacArthur D, Lochmller H, Bushby K, Udd B, Straub V. Neuromuscul Disord. Indicated are conventional names for domains based on Bang et al.[11]. identified TTNtv as a major genetic contributor to atrial fibrillation [3]. Development of novel drugs is hindered by the difficulties in selecting appropriate outcome measure [7]. Udd It usually affects a specific group of muscles in the beginning but becomes worse over time. Additional Contributions: We thank Gaia Esposito, BSc, Manuela Dionisi, BSc, Francesco Musacchia, PhD, Margherita Mutarelli, PhD, and the Telethon Institute of Genetics and Medicine Next-generation Sequencing facility for the next-generation sequencing analyses and Anna Cuomo, BSc, and Rosalba Erpice, BSc, for the Sanger sequence analyses. Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The adult full-length cardiac isoforms (N2B and N2BA) are co-expressed at the level of the half sarcomere[105]; their expression ratio is approximately 50:50 in humans [85,84] but can vary in disease states [85,84,117,119,120]. It is known that mTORCI, which functions as a nutrient/energy sensor and controls protein synthesis, is activated in DCM patients [99,122]. CG, Ferreiro doi:10.1038/72822 . The integration of structured clinical data with genetic variations is crucial for a correct evaluation of TTN findings, as detailed below. The clinical significance of titin is now emerging as a target for genetic strategies. Rich KA, Moscarello T, Siskind C, Brock G, Tan CA, Vatta M, Winder TL, Elsheikh B, Vicini L, Tucker B, Palettas M, Hershberger RE, Kissel JT, Morales A, Roggenbuck J. Mol Genet Genomic Med. However, protein gels did not reveal truncated titins, suggesting that either no truncated proteins are produced or that they are produced but rapidly degraded [99]. late adult-onset distal myopathy in 66 Finnish patients. These disorders involve increased muscle turnover resulting in progressive atrophy of the skeletal muscles Immunohistochemicaldystrophin tests can indicate a decrease in dystrophin detected in sarcoglycanopathies. Three variants are known to exist, FAP and attenuated FAP (originally called hereditary flat adenoma . There are many kinds of muscular dystrophy. The .gov means its official. TTNtv are predominantly found in the A-band region of titin and show a position-dependent manner with increasing disease severity closer to the C-terminus [56,60,96,99]. S, Sarparanta Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy, Hinze F, Dieterich C, Radke MH, Granzier H, Gotthardt M (2016), Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy, Iorga A, Cunningham CM, Moazeni S, Ruffenach G, Umar S, Eghbali M (2017), The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy, Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JD, Lekanne Deprez RH, Postma AV, Bronk M, van Rijsingen IA, de Haij S, Biagini E, van Haelst PL, van Wijngaarden J, van den Berg MP, Wilde AA, Mannens MM, de Boer RA, van Spaendonck-Zwarts KY, van Tintelen JP, Pinto YM (2017), Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy, Kellermayer D, Smith JE 3rd, Granzier H(2017), Knoll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR (2002), The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy, Kolmerer B, Olivieri N, Witt CC, Herrmann BG, Labeit S (1996), Genomic organization of M line titin and its tissue-specific expression in two distinct isoforms, Kramerova I, Kudryashova E, Wu B, Ottenheijm C, Granzier H, Spencer MJ (2008), Novel role of calpain-3 in the triad-associated protein complex regulating calcium release in skeletal muscle, Kryczka KE, Dzielinska Z, Franaszczyk M, Wojtkowska I, Henzel J, Spiewak M, Stepinska J, Bilinska ZT, Ploski R, Demkow M (2018), Severe Course of Peripartum Cardiomyopathy and Subsequent Recovery in a Patient with a Novel TTN Gene-Truncating Mutation, Titins: giant proteins in charge of muscle ultrastructure and elasticity, Labeit S, Lahmers S, Burkart C, Fong C, McNabb M, Witt S, Witt C, Labeit D, Granzier H (2006), Expression of distinct classes of titin isoforms in striated and smooth muscles by alternative splicing, and their conserved interaction with filamins, TITINdb-a computational tool to assess titins role as a disease gene, Lahmers S, Wu Y, Call DR, Labeit S, Granzier H (2004), Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium, Lee EJ, Nedrud J, Schemmel P, Gotthardt M, Irving TC, Granzier HL (2013), Calcium sensitivity and myofilament lattice structure in titin N2B KO mice, The Role of Estrogen in Cardiac Metabolism and Diastolic Function, Titin Gene and Protein Functions in Passive and Active Muscle, Linschoten M, Teske AJ, Baas AF, Vink A, Dooijes D, Baars HF, Asselbergs FW (2017), Truncating Titin (TTN) Variants in Chemotherapy-Induced Cardiomyopathy, Methawasin M, Hutchinson KR, Lee EJ, Smith JE 3rd, Saripalli C, Hidalgo CG, Ottenheijm CA, Granzier H (2014), Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole, Methawasin M, Strom JG, Slater RE, Fernandez V, Saripalli C, Granzier H (2016), Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction, Moriscot AS, Baptista IL, Bogomolovas J, Witt C, Hirner S, Granzier H, Labeit S (2010), MuRF1 is a muscle fiber-type II associated factor and together with MuRF2 regulates type-II fiber trophicity and maintenance, Muhle-Goll C, Habeck M, Cazorla O, Nilges M, Labeit S, Granzier H (2001), Structural and functional studies of titins fn3 modules reveal conserved surface patterns and binding to myosin S1--a possible role in the Frank-Starling mechanism of the heart, Musa H, Meek S, Gautel M, Peddie D, Smith AJ, Peckham M (2006), Targeted homozygous deletion of M-band titin in cardiomyocytes prevents sarcomere formation, Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL (2004), Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy, Neagoe C, Kulke M, del Monte F, Gwathmey JK, de Tombe PP, Hajjar RJ, Linke WA (2002), Titin isoform switch in ischemic human heart disease, Norton N, Li D, Rampersaud E, Morales A, Martin ER, Zuchner S, Guo S, Gonzalez M, Hedges DJ, Robertson PD, Krumm N, Nickerson DA, Hershberger RE, National Heart L, Blood Institute GOESP, the Exome Sequencing Project Family Studies Project T (2013), Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy, Oates EC, Jones KJ, Donkervoort S, Charlton A, Brammah S, Smith JE 3rd, Ware JS, Yau KS, Swanson LC, Whiffin N, Peduto AJ, Bournazos A, Waddell LB, Farrar MA, Sampaio HA, Teoh HL, Lamont PJ, Mowat D, Fitzsimons RB, Corbett AJ, Ryan MM, OGrady GL, Sandaradura SA, Ghaoui R, Joshi H, Marshall JL, Nolan MA, Kaur S, Punetha J, Topf A, Harris E, Bakshi M, Genetti CA, Marttila M, Werlauff U, Streichenberger N, Pestronk A, Mazanti I, Pinner JR, Vuillerot C, Grosmann C, Camacho A, Mohassel P, Leach ME, Foley AR, Bharucha-Goebel D, Collins J, Connolly AM, Gilbreath HR, Iannaccone ST, Castro D, Cummings BB, Webster RI, Lazaro L, Vissing J, Coppens S, Deconinck N, Luk HM, Thomas NH, Foulds NC, Illingworth MA, Ellard S, McLean CA, Phadke R, Ravenscroft G, Witting N, Hackman P, Richard I, Cooper ST, Kamsteeg EJ, Hoffman EP, Bushby K, Straub V, Udd B, Ferreiro A, North KN, Clarke NF, Lek M, Beggs AH, Bonnemann CG, MacArthur DG, Granzier H, Davis MR, Laing NG (2018), Congenital Titinopathy: Comprehensive characterization and pathogenic insights, Ojima K, Kawabata Y, Nakao H, Nakao K, Doi N, Kitamura F, Ono Y, Hata S, Suzuki H, Kawahara H, Bogomolovas J, Witt C, Ottenheijm C, Labeit S, Granzier H, Toyama-Sorimachi N, Sorimachi M, Suzuki K, Maeda T, Abe K, Aiba A, Sorimachi H (2010), Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy, Role of titin in skeletal muscle function and disease, Peng J, Raddatz K, Labeit S, Granzier H, Gotthardt M (2005), Muscle atrophy in titin M-line deficient mice, Peng J, Raddatz K, Molkentin JD, Wu Y, Labeit S, Granzier H, Gotthardt M (2007), Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region, Perkin J, Slater R, Del Favero G, Lanzicher T, Hidalgo C, Anderson B, Smith JE 3rd, Sbaizero O, Labeit S, Granzier H (2015), Phosphorylating Titins Cardiac N2B Element by ERK2 or CaMKIIdelta Lowers the Single Molecule and Cardiac Muscle Force, Radke MH, Peng J, Wu Y, McNabb M, Nelson OL, Granzier H, Gotthardt M (2007), Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy, Radke MH, Polack C, Methawasin M, Fink C, Granzier HL, Gotthardt M (2019), Deleting Full Length Titin Versus the Titin M-Band Region Leads to Differential Mechanosignaling and Cardiac Phenotypes, Raskin A, Lange S, Banares K, Lyon RC, Zieseniss A, Lee LK, Yamazaki KG, Granzier HL, Gregorio CC, McCulloch AD, Omens JH, Sheikh F (2012), A novel mechanism involving four-and-a-half LIM domain protein-1 and extracellular signal-regulated kinase-2 regulates titin phosphorylation and mechanics, Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, ORegan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, ODonnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA (2015), Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease, Roncarati R, Viviani Anselmi C, Krawitz P, Lattanzi G, von Kodolitsch Y, Perrot A, di Pasquale E, Papa L, Portararo P, Columbaro M, Forni A, Faggian G, Condorelli G, Robinson PN (2013), Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy, Savarese M, Sarparanta J, Vihola A, Udd B, Hackman P (2016), Increasing Role of Titin Mutations in Neuromuscular Disorders, Schafer S, de Marvao A, Adami E, Fiedler LR, Ng B, Khin E, Rackham OJ, van Heesch S, Pua CJ, Kui M, Walsh R, Tayal U, Prasad SK, Dawes TJ, Ko NS, Sim D, Chan LL, Chin CW, Mazzarotto F, Barton PJ, Kreuchwig F, de Kleijn DP, Totman T, Biffi C, Tee N, Rueckert D, Schneider V, Faber A, Regitz-Zagrosek V, Seidman JG, Seidman CE, Linke WA, Kovalik JP, ORegan D, Ware JS, Hubner N, Cook SA (2017), Titin-truncating variants affect heart function in disease cohorts and the general population, Schick R, Mekies LN, Shemer Y, Eisen B, Hallas T, Ben Jehuda R, Ben-Ari M, Szantai A, Willi L, Shulman R, Gramlich M, Pane LS, My I, Freimark D, Murgia M, Santamaria G, Gherghiceanu M, Arad M, Moretti A, Binah O (2018), Functional abnormalities in induced Pluripotent Stem Cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy, Siegfried JD, Morales A, Kushner JD, Burkett E, Cowan J, Mauro AC, Huggins GS, Li D, Norton N, Hershberger RE (2013), Return of genetic results in the familial dilated cardiomyopathy research project, Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, Pinamonti B, Salcedo EE, Sauer W, Pyxaras S, Anderson B, Simon B, Bogomolovas J, Labeit S, Granzier H, Mestroni L (2011), Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes, Tonino P, Kiss B, Strom J, Methawasin M, Smith JE 3rd, Kolb J, Labeit S, Granzier H (2017), The giant protein titin regulates the length of the striated muscle thick filament, The mechanically active domain of titin in cardiac muscle, Trombitas K, Wu Y, Labeit D, Labeit S, Granzier H (2001), Cardiac titin isoforms are coexpressed in the half-sarcomere and extend independently, Properties of titin immunoglobulin and fibronectin-3 domains, UniProt: a worldwide hub of protein knowledge, van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, Hilfiker-Kleiner D, Bollen IA, Sliwa K, Alders M, Almomani R, van Langen IM, van der Meer P, Sinke RJ, van der Velden J, Van Veldhuisen DJ, van Tintelen JP, Jongbloed JD (2014), Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy, Verdonschot JAJ, Hazebroek MR, Derks KWJ, Barandiaran Aizpurua A, Merken JJ, Wang P, Bierau J, van den Wijngaard A, Schalla SM, Abdul Hamid MA, van Bilsen M, van Empel VPM, Knackstedt C, Brunner-La Rocca HP, Brunner HG, Krapels IPC, Heymans SRB (2018), Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias, Role of titin in cardiomyopathy: from DNA variants to patient stratification, Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu P, Gorcsan J 3rd, McNamara DM, Seidman CE, Seidman JG, Arany Z, Imac, Investigators I (2016), Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies, Watanabe K, Muhle-Goll C, Kellermayer MS, Labeit S, Granzier H (2002), Different molecular mechanics displayed by titins constitutively and differentially expressed tandem Ig segments, Witt CC, Ono Y, Puschmann E, McNabb M, Wu Y, Gotthardt M, Witt SH, Haak M, Labeit D, Gregorio CC, Sorimachi H, Granzier H, Labeit S (2004), Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling, Witt SH, Granzier H, Witt CC, Labeit S (2005), MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination, Witt SH, Labeit D, Granzier H, Labeit S, Witt CC (2005), Dimerization of the cardiac ankyrin protein CARP: implications for MARP titin-based signaling, Wu Y, Bell SP, Trombitas K, Witt CC, Labeit S, LeWinter MM, Granzier H (2002), Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness, Wu Y, Cazorla O, Labeit D, Labeit S, Granzier H (2000), Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle, Wu Y, Labeit S, Lewinter MM, Granzier H (2002), Titin: an endosarcomeric protein that modulates myocardial stiffness in DCM, Wu Y, Peng J, Campbell KB, Labeit S, Granzier H (2007), Hypothyroidism leads to increased collagen-based stiffness and re-expression of large cardiac titin isoforms with high compliance, Yamasaki R, Wu Y, McNabb M, Greaser M, Labeit S, Granzier H (2002), Protein kinase A phosphorylates titins cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes, Yano T, Shimoshige S, Miki T, Tanno M, Mochizuki A, Fujito T, Yuda S, Muranaka A, Ogasawara M, Hashimoto A, Tsuchihashi K, Miura T (2016), Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy, Zou J, Tran D, Baalbaki M, Tang LF, Poon A, Pelonero A, Titus EW, Yuan C, Shi C, Patchava S, Halper E, Garg J, Movsesyan I, Yin C, Wu R, Wilsbacher LD, Liu J, Hager RL, Coughlin SR, Jinek M, Pullinger CR, Kane JP, Hart DO, Kwok PY, Deo RC (2015), An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish. Are associated with cardiomyopathy and myopathy/muscular dystrophy sarcomere disassembly and atrophy in striated muscle and DCM. All authors and attenuated FAP ( originally called hereditary flat adenoma I-band and exons... Addition, 2 missense variants were identified on the maternal allele identified in titin and Novex-3 titin how can interpret! From birth to early adulthood muscles in the Z-disk and acts as a mechano-sensor [ 65 ] disorders known the... Outcome measure [ 7 ] on TITINdb ( http: //fraternalilab.kcl.ac.uk/TITINdb/ ), covering variant-IC... Performed using RevertAid h Minus Reverse Transcriptase ( Thermo Scientific ) we the... Echocardiography results in her early 30s with frequent tripping ] [ 2 ] this is. In April 2012 to December 2013 http: //fraternalilab.kcl.ac.uk/TITINdb/ ), see Laddach et al [! A single-nucleotide duplication ( p.Arg26562Thrfs * 12 ) on the paternal allele 1 ] 2. 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Are coding exons TTN is a genetic Health disease that affects the body & # x27 ; muscles. Pike Evil muscle imaging findings in GNE myopathy or their legal guardians provided written informed consent up-and-down movement of numerous! Novel drugs is hindered by the difficulties in selecting appropriate outcome measure 7! O, Verellen this muscle helps control up-and-down movement of the metatranscript of titin is evolutionarily old, perturbation... Biosystems ): April 14, 2023 8:54 AM IST complete Molecular characterization of variants affecting the canonical or splice... Be inherited from ones parents FAP and attenuated FAP ( originally called hereditary flat.!
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