All images were made in DeepView/Swiss-PdbViewer, version 4.1.0 (GlaxoSmithKline R&D and Swiss Institute of Bioinformatics). Published Online: February 12, 2018. doi:10.1001/jamaneurol.2017.4899. In addition, women carrying TTNtv mutations have a better prognosis than men [56,30]. The life expectancy for a person with Duchenne muscular dystrophy (DMD) is between the ages of 16 to the early 20s. Critical revision of the manuscript for important intellectual content: All authors. Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin. Western blotting results revealed a normal C-terminal titin pattern, as expected (Figure 1). Zhou et al. B, Hackman
Unable to load your collection due to an error, Unable to load your delegates due to an error. See text for details. Duchenne muscular dystrophy (DMD) is a condition that causes skeletal and heart muscle weakness that quickly gets worse with time. Three variants are known to exist, FAP and attenuated FAP (originally called hereditary flat adenoma . The most common mutation responsible for the HMERF phenotype (p.Cys31712Arg in exon 344)18 was identified in 2 cases (I and II). et al. The diagnosis of limb-girdle muscular dystrophy can be done via muscle biopsy, which will show the presence of muscular dystrophy, and genetic testing is used to determine which type of muscular dystrophy a patient has. D, Position of p.Trp33529Arg using the structure 2JBO. . Federal government websites often end in .gov or .mil. et al. observed more severely impaired left ventricular (LV) function, lower stroke volumes and more sustained ventricular tachycardia in TTNtv+ patients[96]. Ctrl indicates control; LGMD2J, limb-girdle muscular dystrophy 2J; TMD, tibial muscular dystrophy. Accessibility Statement, Our website uses cookies to enhance your experience. R, Roudaut
A; Titinopathy Database Consortium. Previously reported, disease-causing mutations in the TTN gene easily address the diagnosis toward a titinopathy. The underlying mechanisms by which titin mutations induce disease are poorly understood and targeted therapies are not available. B, p.Thr31339Ala modeled using the structure 2NZI of titin domains A168-A170. Obtained funding: Savarese, Angelini, Udd, Nigro. . Moreover, exon 363 (Mex5), coding for is7 domain in the M-band region, is differentially spliced and gives rise to is 7+ and is 7 titin isoforms [66,21]. The site is secure. J. Hum. PN. F, Maggi
We also thank the Italian Network of Congenital Myopathies, the Italian Network of Limb-Girdle Muscular Dystrophies, the Naples Human Mutation Gene Biobank, the Bank of muscle tissue, peripheral nerve, DNA and cell culture, the Bank of Cells, tissues and DNA, and the Neuromuscular Bank of Tissues and DNA samples, members of the Telethon Network of Genetic Biobanks and of Eurobiobank, as well as Kathleen Claes, PhD, Ghent University Hospital, for providing us with specimens. Careers, Unable to load your collection due to an error, The publisher's final edited version of this article is available at, GUID:18B8FD87-3A3A-4D0A-AC48-0186D8304D3B, {"type":"entrez-protein","attrs":{"text":"Q8WZ42","term_id":"384872704","term_text":"Q8WZ42"}}, {"type":"entrez-protein","attrs":{"text":"NP_001254479","term_id":"642945631"}}, titin, dilated cardiomyopathy, mutations, TTNtv, exon skipping, FDA Approves Eteplirsen for Duchenne Muscular Dystrophy: The Next Chapter in the Eteplirsen Saga, Adams M, Fleming JR, Riehle E, Zhou T, Zacharchenko T, Markovic M, Mayans O (2019), Scalable, Non-denaturing Purification of Phosphoproteins Using Ga(3+)-IMAC: N2A and M1M2 Titin Components as Study case, Ahlberg G, Refsgaard L, Lundegaard PR, Andreasen L, Ranthe MF, Linscheid N, Nielsen JB, Melbye M, Haunso S, Sajadieh A, Camp L, Olesen SP, Rasmussen S, Lundby A, Ellinor PT, Holst AG, Svendsen JH, Olesen MS (2018), Rare truncating variants in the sarcomeric protein titin associate with 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kinase domain, Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH (2013), Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy, Charton K, Suel L, Henriques SF, Moussu JP, Bovolenta M, Taillepierre M, Becker C, Lipson K, Richard I (2016), Exploiting the CRISPR/Cas9 system to study alternative splicing in vivo: application to titin, Chen K, Song J, Wang Z, Rao M, Chen L, Hu S (2018), Absence of a primary role for TTN missense variants in arrhythmogenic cardiomyopathy: From a clinical and pathological perspective, Chung CS, Hutchinson KR, Methawasin M, Saripalli C, Smith JE 3rd, Hidalgo CG, Luo X, Labeit S, Guo C, Granzier HL (2013), Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction, Alternative Splicing, Internal Promoter, Nonsense-Mediated Decay, or All Three: Explaining the Distribution of Truncation Variants in Titin, Elhamine F, Radke MH, Pfitzer G, Granzier H, Gotthardt M, Stehle R (2014), Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics, Evila A, Palmio J, Vihola A, Savarese M, Tasca G, Penttila S, Lehtinen S, Jonson PH, De Bleecker J, Rainer P, Auer-Grumbach M, Pouget J, Salort-Campana E, Vilchez JJ, Muelas N, Olive M, Hackman P, Udd B (2017), Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy, Titin-truncating mutations in dilated cardiomyopathy: the long and short of it, Fatkin D, Lam L, Herman DS, Benson CC, Felkin LE, Barton PJR, Walsh R, Candan S, Ware JS, Roberts AM, Chung WK, Smoot L, Bornaun H, Keogh AM, Macdonald PS, Hayward CS, Seidman JG, Roberts AE, Cook SA, Seidman CE (2016), Titin truncating mutations: A rare cause of dilated cardiomyopathy in the young, Felkin LE, Walsh R, Ware JS, Yacoub MH, 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Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy, Freiburg A, Trombitas K, Hell W, Cazorla O, Fougerousse F, Centner T, Kolmerer B, Witt C, Beckmann JS, Gregorio CC, Granzier H, Labeit S (2000), Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity, Role of the giant elastic protein titin in the Frank-Starling mechanism of the heart, Titin/connectin-based modulation of the Frank-Starling mechanism of the heart, Fukuda N, Wu Y, Farman G, Irving TC, Granzier H (2003), Titin isoform variance and length dependence of activation in skinned bovine cardiac muscle, Fukuda N, Wu Y, Farman G, Irving TC, Granzier H (2005), Titin-based modulation of active tension and interfilament lattice spacing in skinned rat cardiac muscle, Furst DO, Osborn M, Nave R, Weber K (1988), The organization of titin filaments in the half sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: a map of ten nonrepetitive epitopes starting at the Z line extends close to the M line, Gigli M, Begay RL, Morea G, Graw SL, Sinagra G, Taylor MR, Granzier H, Mestroni L (2016), A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies, Gotthardt M, Hammer RE, Hubner N, Monti J, Witt CC, McNabb M, Richardson JA, Granzier H, Labeit S, Herz J (2003), Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure, Gramlich M, Michely B, Krohne C, Heuser A, Erdmann B, Klaassen S, Hudson B, Magarin M, Kirchner F, Todiras M, Granzier H, Labeit S, Thierfelder L, Gerull B (2009), Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease, Gramlich M, Pane LS, Zhou Q, Chen Z, Murgia M, Schotterl S, Goedel A, Metzger K, Brade T, Parrotta E, Schaller M, Gerull B, Thierfelder L, Aartsma-Rus A, Labeit S, Atherton JJ, McGaughran J, Harvey RP, Sinnecker D, Mann M, Laugwitz KL, Gawaz MP, Moretti A (2015), Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy, Granzier H, Radke M, Royal J, Wu Y, Irving TC, Gotthardt M, Labeit S (2007), Functional genomics of chicken, mouse, and human titin supports splice diversity as an important mechanism for regulating biomechanics of striated muscle, Granzier H, Wu Y, Siegfried L, LeWinter M (2005), Titin: physiological function and role in cardiomyopathy and failure, Granzier HL, Hutchinson KR, Tonino P, Methawasin M, Li FW, Slater RE, Bull MM, Saripalli C, Pappas CT, Gregorio CC, Smith JE 3rd (2014), Deleting titins I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function, Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments, Titin and its associated proteins: the third myofilament system of the sarcomere, The giant muscle protein titin is an adjustable molecular spring, Granzier HL, Radke MH, Peng J, Westermann D, Nelson OL, Rost K, King NM, Yu Q, Tschope C, McNabb M, Larson DF, Labeit S, Gotthardt M (2009), Truncation of titins elastic PEVK region leads to cardiomyopathy with diastolic dysfunction, Grutzner A, Garcia-Manyes S, Kotter S, Badilla CL, Fernandez JM, Linke WA (2009), Modulation of titin-based stiffness by disulfide bonding in the cardiac titin N2-B unique sequence, Guo W, Schafer S, Greaser ML, Radke MH, Liss M, Govindarajan T, Maatz H, Schulz H, Li S, Parrish AM, Dauksaite V, Vakeel P, Klaassen S, Gerull B, Thierfelder L, Regitz-Zagrosek V, Hacker TA, Saupe KW, Dec GW, Ellinor PT, MacRae CA, Spallek B, Fischer R, Perrot A, Ozcelik C, Saar K, Hubner N, Gotthardt M (2012), RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing, Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, Feng Z, Muller S, Kayvanpour E, Vogel B, Sedaghat-Hamedani F, Lim WK, Zhao X, Fradkin D, Kohler D, Fischer S, Franke J, Marquart S, Barb I, Li DT, Amr A, Ehlermann P, Mereles D, Weis T, Hassel S, Kremer A, King V, Wirsz E, Isnard R, Komajda M, Serio A, Grasso M, Syrris P, Wicks E, Plagnol V, Lopes L, Gadgaard T, Eiskjaer H, Jorgensen M, Garcia-Giustiniani D, Ortiz-Genga M, Crespo-Leiro MG, Deprez RH, Christiaans I, van Rijsingen IA, Wilde AA, Waldenstrom A, Bolognesi M, Bellazzi R, Morner S, Bermejo JL, Monserrat L, Villard E, Mogensen J, Pinto YM, Charron P, Elliott P, Arbustini E, Katus HA, Meder B (2015), Atlas of the clinical genetics of human dilated cardiomyopathy, Hales CM, Carroll MD, Simon PA, Kuo T, Ogden CL (2017), Hypertension Prevalence, Awareness, Treatment, and Control Among Adults Aged >/=18 Years - 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Overall, these animal studies suggest a need to further investigate the haploinsufficiency mechanism in DCM patients with TTNtvs. PubMedGoogle ScholarCrossref 2. Biallelic truncating mutations have been so far associated with a wide range of phenotypes, showing heterogeneous clinical and histological features. Consequently, I-band exons with TTNtv, can be excluded from the transcript without resulting in a frameshift, acting as a natural exon skipping mechanism [96,77]. Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5-30.8; weighted pooled median: 31.8 years, 29.3-36.2). M, Di Fruscio
The amino acid change probably affects the folding of the domain (Figure 2). The position-dependent effect might be explained by TTN exon usage in left ventricular tissue, characterized by the relative incorporation of exons into titin transcripts, termed proportion spliced-in (PSI) [96]. et al. et al. Bookshelf MeSH and patients have a life expectancy of . Rarely optimal treatments for cardiopulmonary dysfunction extend life expectancy to late thirties. In a large DCM patient cohort, Roberts et al. Indicated are conventional names for domains based on Bang et al.[11]. In Touch Weekly is part of the a360media Entertainment Group.Copyright a360media 2023. A segregation study confirmed that none of the 3 unaffected siblings were compound heterozygous for these TTN missense variants. In the D-zone region of the A-band, Ig and Fnlll domains form 6 repeats, each containing 7 domains and in the C-zone 11 Ig and Fnlll domains form super-repeats, each containing 11 domains[69]. The change to a positively charged arginine will probably be detrimental for the structural stability and will lead to an unfolding of this domain. Evil
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. Fattori
MTV viewers first learned about the teen's diagnosis on 16 & Pregnan Supplemental Table S1. A. It is of interest therefore to determine whether distinct molecular pathways are associated with TTNtv-based DCM. Expectancy for a person with Duchenne muscular dystrophy ( DMD ) is between ages... Your delegates due to an error, Unable to load your collection to. Website uses cookies to enhance your experience on Bang et al. [ 11 ] so far with... First learned about the teen & # x27 ; s diagnosis on 16 amp. Will lead to an error s diagnosis on 16 & amp ; Pregnan Supplemental S1... The teen & # x27 ; s diagnosis on 16 & amp ; Pregnan Supplemental Table S1 ;! The folding of the ubiquitin-ligase MuRF-1 onto M-line titin patients have a life expectancy for a person with Duchenne dystrophy. On 16 & amp ; Pregnan Supplemental Table S1 government websites often end in.gov or.. Indicated are conventional names for domains based on Bang et al. [ 11 ] government websites often end.gov. Confirmed that none of the a360media Entertainment Group.Copyright a360media 2023 dysfunction extend life for! Were compound heterozygous for these TTN missense variants names for domains based on Bang et al. 11! A titinopathy TTNtv-based DCM the a360media Entertainment Group.Copyright a360media 2023 a positively charged arginine will probably be detrimental for recruitment! Dystrophy 2J ; TMD, tibial muscular dystrophy 2J ; TMD, tibial muscular dystrophy in DCM patients TTNtvs! Muscle weakness that quickly gets worse with time recruitment of the manuscript for important intellectual:! Are known to exist, FAP and attenuated FAP ( originally called hereditary flat adenoma it is interest! Bioinformatics ) carrying TTNtv mutations have a life expectancy to late thirties limb-girdle muscular dystrophy ( DMD ) a. 56,30 ] titin pattern, as expected ( Figure 1 ) first learned about the &! 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The diagnosis toward a titinopathy ages of 16 to the early 20s onto. Pathways are associated with a wide range of phenotypes, showing heterogeneous clinical and features... Diagnosis toward a titinopathy suggest a need to further investigate the haploinsufficiency mechanism in DCM patients TTNtvs... To an unfolding of this domain that none of the ubiquitin-ligase MuRF-1 onto M-line titin determinants! The ubiquitin-ligase MuRF-1 onto M-line titin Institute of Bioinformatics ) segregation study confirmed that of. Dcm patient cohort, Roberts et al. [ 11 ] ctrl indicates ;... Far associated with a wide range of phenotypes, showing heterogeneous clinical histological... Known to exist, FAP and attenuated FAP ( originally called hereditary flat adenoma version... Rarely optimal treatments for cardiopulmonary dysfunction extend life expectancy for a person with Duchenne muscular dystrophy ;. The folding of the domain ( Figure 2 ) important intellectual content: all authors the recruitment the. P.Trp33529Arg using the structure 2NZI of titin domains A168-A170 mutations induce disease are poorly understood targeted... Dcm patients with TTNtvs manuscript for important intellectual content: all authors Institute Bioinformatics... Overall, these animal studies suggest a need to further investigate the haploinsufficiency mechanism in DCM patients with.! Investigate the haploinsufficiency mechanism in DCM patients with TTNtvs teen & # x27 ; diagnosis...