Bang We propose a specific workflow for the clinical interpretation of genetic findings in titin. Genet. In this case series, 504 patients with skeletal muscle disorders were screened with a targeted resequencing approach. A, Sarparanta Life expectancy is not thought to be affected by this form of muscular dystrophy. Acquisition, analysis, or interpretation of data: All authors. S, Life Expectancy in Duchenne Muscular Dystrophy: Reproduced Individual Patient Data Meta-analysis This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fattori My heartttt #itsthelittlethings #softball #coachpitch #love #aligirl #mygirl #mdwontstopher, A post shared by @ @ (@leahdawn92mtv) on Apr 23, 2018 at 12:49pm PDT. Most patients need wheelchair and assisted ventilation before the age of 20. Robinson Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. Schafer et. Mutations of TTN are causally related to specific types of muscular dystrophies and cardiomyopathies. 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. 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). et al. The change to a positively charged arginine will probably be detrimental for the structural stability and will lead to an unfolding of this domain. PPCM can also be a manifestation of familial DCM and TTNtv in PPCM patients is a possible prognostic factor for low recovery rate [108,112]. MC. In addition, 2 missense variants were identified on the paternal allele. Dystrophin acts like a shock absorber when muscles contract. Because of its size, many rare or private variants are usually identified in the titin gene by NGS analyses.5 The correct interpretation of these variants is a critical challenge for making a diagnosis for patients affected by neuromuscular disorders.5 Although mainly truncating mutations have been identified in patients with titinopathy, missense variants may similarly have a crucial role, as also suggested by our data (Figure 3). N, Bhm Conflict of Interest Disclosures: None reported. 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]. Several recent studies suggest that heterozygous titin truncating variants cause dominant dilated cardiomyopathy.40,41 However, a positional effect and an incomplete and age-dependent penetrance (probably related to other genetic or environmental factors) may explain the lack of any cardiac symptoms in some individuals with mono or biallelic PTVs (eg, patient V and VIII).41 A systematic follow-up to evaluate the cardiac status of such individuals, as well as their asymptomatic relatives who carry truncating variants, is highly recommended. Richards Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Accession numbers for the Metatranscript and Novex-3 proteins are {"type":"entrez-protein","attrs":{"text":"NP_001254479","term_id":"642945631"}}NP_001254479 and NP 596870. However, the definitive proof of pathogenicity for missense variants can only be established by functional tests, segregation studies in very large families, and/or identifying unrelated patients or families with the same mutations. DCM is characterized by left ventricular dilation and systolic dysfunction [57]. Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. However, a complete molecular characterization of variants affecting the canonical or noncanonical splice sites by cDNA or protein studies is suggested. A, Schematic visualization of truncating (circle) and missense (triangle) variants identified in TTN gene in this study. Would you like email updates of new search results? Before Krger M, Ktter Front Physiol. To date, there are contradictory observations in patient populations about the symptoms and differences between DCM patients with (TTNtv+) or without (TTNtv) mutations. Moreira, E. S. et al. Ali was diagnosed with Titin Myotonic muscular dystrophy in 2014, a rare form of progressive weakness disease that had existed in less than 20 cases around the world at the time of her diagnosis. et al. Symptoms of the most common variety begin in childhood, mostly in boys. To identify genetic variants in titin in a cohort of patients with muscle disorders. First, we enrolled, in a multicenter study, patients with clinically and genetically heterogenous conditions and specific clinical studies (magnetic resonance imaging or cardiac tests) were unavailable or not performed for some patients. et al. Muscular dystrophies ( MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. Symptoms usually show up around your 20s or 30s, but they can happen at any age. There are many kinds of muscular dystrophy. Duchenne muscular dystrophy is a rare, genetic condition that is characterized by progressive muscle damage and weakness. L, Taylor Because rare missense variants were found in most analyzed patients, we focused on a single recessive family (family X) in whom 2 rare variants segregated with the observed phenotype. 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. et al. Importance G, Ricci Nigro He presented with a progressive distal weakness in the lower limbs (onset at 40 years) and a restrictive respiratory insufficiency due to respiratory muscle weakness. However, Alis parents have made sure that they wont let her condition slow her down, and on countless occasions, theyve praised her for being an inspiration. The possible role of titin variants as modifiers or within a digenic or multigenic disease is not discussed here. The average lifespan for Duchenne muscular dystrophy is 18 to 25 years. R, Roudaut National Library of Medicine Patient I was a man in his late 50s with no family history for neuromuscular disorders. A, Carrascosa-Romero D, Witt He had delayed motor milestones, reaching independent walking after the toddler years. Due to its enormous size, TTN has been insufficiently analyzed in the past. 2019;90:1-23. doi: 10.1016/bs.acc.2019.01.001. B, Hackman Genet. Multiple mechanisms have been proposed to explain TTNtv-induced DCM: haploinsufficiency, poison-peptide/dominant-negative mechanism, and perturbation of cardiac metabolism and signaling. Furthermore, mutated cells display a longer recovery period after caffeine administration [100]. C, B, Partanen By clicking Sign Up, you agree to our Terms and Conditions and that you have read our Privacy Policy. Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine.While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated. 2001;89(11):1065-1072. In muscular dystrophy, abnormal genes (mutations) interfere with the production of proteins needed to form healthy muscle. eFigure. Indicated are conventional names for domains based on Bang et al.[11]. To fully characterize the natural history, it is crucial to obtain appropriate estimates of the life expectancy and mortality rates of . Western blotting results revealed a normal C-terminal titin pattern, as expected (Figure 1). Duchenne and Becker muscular dystrophy. Extensive mRNA splicing results in distinct titin isoforms [11,70] (Figure 1). R, Straub generated a conditional KO mouse model with progressive postnatal loss of the complete titin protein achieved by removing exon 2 (E2-KO)[94]. Furthermore, patients with TTNtv are at higher risk to more adverse cardiac events, as death, cardiac transplant, or LV assist device [96]. Now, an expert who has never treated Ali is weighing in on her condition. M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. [1] [2] This condition is less common and less severe than Duchenne muscular dystrophy (DMD). John E. Smith declares that he has no conflicts of interest. Of the 4 other patients (3 men and 1 woman) with possibly disease-causing. Most mutations that alter titin's characteristics seem to be incompatible with life, since very few associated genetic diseases have been described. 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 familial and early-onset atrial fibrillation, Ait-Mou Y, Hsu K, Farman GP, Kumar M, Greaser ML, Irving TC, de Tombe PP (2016), Titin strain contributes to the Frank-Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins, Akinrinade O, Alastalo TP, Koskenvuo JW (2016), Relevance of truncating titin mutations in dilated cardiomyopathy, Akinrinade O, Koskenvuo JW, Alastalo TP (2015), Prevalence of Titin Truncating Variants in General Population, Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenpera P, Koillinen H, Kaartinen M, Nieminen MS, Myllykangas S, Alastalo TP, Koskenvuo JW, Helio T (2015), Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy, Alegre-Cebollada J, Kosuri P, Giganti D, Eckels E, Rivas-Pardo JA, Hamdani N, Warren CM, Solaro RJ, Linke WA, Fernandez JM (2014), S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding, Anderson BR, Bogomolovas J, Labeit S, Granzier H (2013), Single molecule force spectroscopy on titin implicates immunoglobulin domain stability as a cardiac disease mechanism, Titin-based tension in the cardiac sarcomere: molecular origin and physiological adaptations, Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (2001), 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, Emerging importance of oxidative stress in regulating striated muscle elasticity, Begay RL, Graw S, Sinagra G, Merlo M, Slavov D, Gowan K, Jones KL, Barbati G, Spezzacatene A, Brun F, Di Lenarda A, Smith JE, Granzier HL, Mestroni L, Taylor M, Familial Cardiomyopathy R (2015), Role of Titin Missense Variants in Dilated Cardiomyopathy, Titin domain patterns correlate with the axial disposition of myosin at the end of the thick filament, Brynnel A, Hernandez Y, Kiss B, Lindqvist J, Adler M, Kolb J, van der Pijl R, Gohlke J, Strom J, Smith J, Ottenheijm C, Granzier HL (2018), Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy, Burke MA, Cook SA, Seidman JG, Seidman CE (2016), Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy, Cazorla O, Freiburg A, Helmes M, Centner T, McNabb M, Wu Y, Trombitas K, Labeit S, Granzier H (2000), Differential expression of cardiac titin isoforms and modulation of cellular stiffness, Cazorla O, Wu Y, Irving TC, Granzier H (2001), Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes, Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S (2001), Identification of muscle specific ring finger proteins as potential regulators of the titin 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, Birks EJ, Barton PJ, Cook SA (2016), Recovery of Cardiac Function in Cardiomyopathy Caused by Titin Truncation, Franaszczyk M, Chmielewski P, Truszkowska G, Stawinski P, Michalak E, Rydzanicz M, Sobieszczanska-Malek M, Pollak A, Szczygiel J, Kosinska J, Parulski A, Stoklosa T, Tarnowska A, Machnicki MM, Foss-Nieradko B, Szperl M, Sioma A, Kusmierczyk M, Grzybowski J, Zielinski T, Ploski R, Bilinska ZT (2017), Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations, A molecular map of the interactions between titin and myosin binding protein C. 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 - Los Angeles County, 1999-2006 and 2007-2014, Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes, Hamdani N, Krysiak J, Kreusser MM, Neef S, Dos Remedios CG, Maier LS, Kruger M, Backs J, Linke WA (2013), Crucial role for Ca2(+)/calmodulin-dependent protein kinase-II in regulating diastolic stress of normal and failing hearts via titin phosphorylation, Helmes M, Trombitas K, Centner T, Kellermayer M, Labeit S, Linke WA, Granzier H (1999), Mechanically driven contour-length adjustment in rat cardiac titins unique N2B sequence: titin is an adjustable spring, Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG, Seidman CE (2012), Truncations of titin causing dilated cardiomyopathy, Hershberger RE, Hedges DJ, Morales A (2013), Dilated cardiomyopathy: the complexity of a diverse genetic architecture, Tuning the molecular giant titin through phosphorylation: role in health and disease, Hidalgo CG, Chung CS, Saripalli C, Methawasin M, Hutchinson KR, Tsaprailis G, Labeit S, Mattiazzi A, Granzier HL (2013), The multifunctional Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIdelta) phosphorylates cardiac titins spring elements, Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, Gorham J, Yang L, Schafer S, Sheng CC, Haghighi A, Homsy J, Hubner N, Church G, Cook SA, Linke WA, Chen CS, Seidman JG, Seidman CE (2015), HEART DISEASE.