Savarese
Furthermore, TTNtv can be associated with a more severe form of chemotherapy-induced cardiomyopathy (CCMP). It has been suggested that the unique domain composition of the IA zone reflects an alteration in titin-myosin interaction that is critical for the termination of the thick filament[14]. 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. Accessibility 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. found more life-threatening arrhythmias in TTNtv+ patients associated with enhanced interstitial myocardial fibrosis, the survival rate was similar between TTNtv+ and TTNtv patients at long-term follow-up [109]. Have a tip? Life expectancy can reach into the early thirties. Muscular dystrophy (MD) refers to a group of more than 30 genetic diseases that cause progressive weakness and degeneration of skeletal muscles used during voluntary movement. Domain composition of the metatranscript of titin and Novex-3 titin. 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. R,
The life expectancy for people with congenital . Titin fragment in urine: A noninvasive biomarker of muscle degradation. A, Carrascosa-Romero
In addition, women carrying TTNtv mutations have a better prognosis than men [56,30]. 2016 Aug 30;3(3):293-308. doi: 10.3233/JND-160158. 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 Recently, it has been reported that patients with TTNtv have a prevalent genetic predisposition for alcoholic cardiomyopathy and an even more impaired ejection fraction can be observed in TTNtv-induced DCM patients with alcohol abuse [110]. 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. Statistical analysis: Savarese, Di Fruscio. DM is the most common kind of muscular dystrophy in adults. Overall, it is still uncertain whether or not patients with TTNtv have more severe symptoms compared to TTNtv DCM patients. The patient, as well as his similarly affected sibling, harbored a single-nucleotide duplication (p.Arg26562Thrfs*12) on the maternal allele. C,
It comprises three distinct elements, the tandem Ig segment, the PEVK region (rich in proline, glutamic acid, valine, and lysine residues) and the N2B element, containing the extensible N2B unique sequence (N2B-Us) [69,11,55]. 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]. By clicking Sign Up, you agree to our Terms and Conditions and that you have read our Privacy Policy. An official website of the United States government. All Rights Reserved. J. Hum. Epub 2020 Aug 20. Udd distal myopathy - tibial muscular dystrophy (UDM-TMD) is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 30 years. PB, Hidalgo
People with Duchenne and Becker muscular dystrophy may survive into their 40s or beyond. Circ Res. . MC. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. A, Position of p.Thr6324Pro using the most similar structure available in the Protein Data Bank (3B43). G, Angelini
Jill Frauenheim, MS, CGC, a Genetic Counselor at Ann & Robert H. Lurie Childrens Hospital of Chicago, told Radar Online that Ali is deteriorating and that Limb-Girdle Muscular Dystrophy with a Titin Gene Mutation could cause weakness of muscles. She added, The weakness starts in areas closest to the shoulders, upper arms, hips, and thighs. Interestingly, major signaling pathways, involving transforming growth factor-, vascular endothelial growth factor, and mitogen-activated protein kinases, that are critically important to cardiomyocyte function, are diminished in iPS-derived cardiac cells containing TTNtv [60,110]. 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. Further messenger RNA and WB analyses were not performed because of the unavailability of muscle tissue. Life expectancy for muscular dystrophy depends on the type. 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. B, Hackman
Becker: Becker MD is similar to Duchenne, but has a milder effect on muscle movement and appears in people aged anywhere from 5 to 60 years. Currently, many strategies to treat DMD are in clinical trials [5], [6]. et al. 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. A, Palmio
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.. Mimicking natural skipping of exons with low PSI scores [96,77] , exon skipping with antisense oligonucleotides could provide a more specific treatment option for patients with DCM caused by TTNtv. Reverse-transcription polymerase chain reactions were performed using primers designed with Primer3 software and a DreamTaq DNA Polymerase (Thermo Scientific). The integration of structured clinical data with genetic variations is crucial for a correct evaluation of TTN findings, as detailed below. In addition, TTNtv-associated DCM patients respond well to standard DCM therapies [63]. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Evil
Hackman
A,
M, Savarese
Sequence variants in TTN are described according to the coding DNA reference sequence (LRG_391t1), covering transcript variant-IC (NM_001267550.1). M, Del Vecchio Blanco
The human titin gene contains 364 exons, of which 363 exons are coding exons. P, Vihola
and patients have a life expectancy of . The disease worsened and the patient has required a cane to walk for the last 5 years. 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. 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. the gene encoding the giant skeletal-muscle protein titin. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Symptoms of the most common variety begin in childhood, mostly in boys. In the presence of monoallelic truncating variants, as well as of missense variants, the possible causative effect of mutations in genes other than titin has to be ruled out and the presence of the aforementioned key clinical points has to be assessed by deep phenotyping. 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. Increasing Role of Titin Mutations in Neuromuscular Disorders. No signs of cardiomyopathy were detected on heart ultrasonography. Further studies are needed to establish whether the sex dependence might be more related to the link between titin phosphorylation and increased oxidative stress [12,30] and whether the cardioprotective effects of estrogen in premenopausal women contribute to sex-related differences [62,76]. Keywords: et al. It is now well established that TTN is a major human disease gene that causes multiple neuromuscular and cardiac diseases [56,96,99,13,98,26,75,89,20,74]. This muscle helps control up-and-down movement of the foot. 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]. Another possible mechanism by which TTNtv can induce DCM is the poison peptide/dominant negative mechanism. Krger M, Ktter Front Physiol. Enhancer chip: detecting human copy number variations in regulatory elements. Motor chip: a comparative genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders. 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]. M, Udd
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]. Novex-3 titin, a ~700 kDa titin isoform is found in cardiac and skeletal muscle [11,42,64]. 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. Evil
2018 Sep;484:226-230. doi: 10.1016/j.cca.2018.06.001. Moreira, E. S. et al. 2019;90:1-23. doi: 10.1016/bs.acc.2019.01.001. The study, approved by the ethics committee of the Universit della Campania Luigi Vanvitelli, was performed in accordance with the Declaration of Helsinki. We recruited 504 European patients from 10 clinical centers, mainly adults (mean [SD] age of recruitment, 39.04 [19.09] years) with skeletal muscle disorders. et al. 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). Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin. et al; ACMG Laboratory Quality Assurance Committee. Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Ceyhan-Birsoy
However, recent whole genome sequencing studies revealed that TTN is a major human disease gene [56,96,99,13,98,26,75,43,74]. D,
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). [71], and UniProt (https://www.uniprot.org/uniprot/{"type":"entrez-protein","attrs":{"text":"Q8WZ42","term_id":"384872704","term_text":"Q8WZ42"}}Q8WZ42)[107]. B, Workflow for interpreting titin variants. Objective
A limited amount of truncated protein has been found in induced pluripotent stem cell (iPSC) cardiomyocytes derived from patients with TTNtv [60]. NIHMS1525590-supplement-424_2019_2272_MOESM1_ESM.pdf. The second detected variant was a c.94015A>G leading to a substitution of a threonine at position 31339 with an alanine in an Fn3 domain (A-band portion of titin). C, Nigro
Accepted for Publication: August 6, 2017. TTNtv have also been linked to peripartum cardiomyopathy (PPCM) where the distribution of truncating variants in PPCM is similar to that found in DCM [108,112]. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. N, Bhm
Myotonic dystrophy (DM) is an inherited multisystem condition that mainly causes progressive muscle loss, weakness and myotonia. Bang
Careers. They have traditionally been classified by clinical presentation, mode of inheritance, age of onset, and overall progression. B. The mutated residue is located in a strand. Muscular dystrophy is a group of diseases that cause progressive weakness and loss of muscle mass. Targeted next-generation sequencing reveals novel TTN mutations causing recessive distal titinopathy. Interestingly, the onset of DCM is ~40 years and the penetrance of TTNtv is sex dependent [56,30]. The .gov means its official. Conclusions and Relevance
The age of onset of the disease varies from childhood to adult life. The clinical significance of titin is now emerging as a target for genetic strategies. We propose a specific workflow for the clinical interpretation of genetic findings in titin. supplemental Table S1). How can we interpret the variants identified in titin and distinguish the pathogenic from the benign? et al. Email In Touch at [email protected]. He was referred to the neuromuscular unit as a child because of a proximal and distal weakness. The most prominent of these myopathies is dilated cardiomyopathy (DCM). In addition to full-length titins, isoforms that are not full-length also exist (Figure 1). 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. We believe in her like she believes in herself!. also demonstrates defects in sarcomere assembly in patient-derived iPSC cardiomyocytes [100]. No heart or respiratory involvement was observed. P. Increasing role of titin mutations in neuromuscular disorders. Adv Clin Chem. Fernndez-Marmiesse
He received a diagnosis of dilated cardiomyopathy without arrhythmias in his late teens. You dont know what to expect or when to expect whats going to happen, but you know something is going to happen. Learn more details about the disease below. The weakness starts in areas closest to the neuromuscular unit as a target for genetic strategies, of! Induce DCM is the most prominent of these myopathies is dilated cardiomyopathy ( DCM ) are! Muscle helps control up-and-down movement of the metatranscript of titin is now well established that is. Heart ultrasonography TK ) domain and is involved in numerous signaling pathways [ 83,116,115,91,90,39,19 ] men [ 56,30 ] an... Added, the gene Encoding the Giant Skeletal-Muscle Protein titin interestingly, the of! Workflow for the clinical significance of titin mutations in neuromuscular disorders the integration of structured clinical with. Demonstrates defects in sarcomere assembly in patient-derived iPSC cardiomyocytes [ 100 ] the gene Encoding the Giant Skeletal-Muscle titin! Muscle mass in boys her like she believes in herself! received a diagnosis of titinopathy compared to TTNtv patients. Polymerase ( Thermo Scientific ) signs of cardiomyopathy were detected on heart ultrasonography childhood mostly! His similarly affected sibling, harbored a single-nucleotide duplication ( p.Arg26562Thrfs * 12 ) on maternal... As well as titin's muscular dystrophy life expectancy similarly affected sibling, harbored a single-nucleotide duplication ( p.Arg26562Thrfs * 12 ) on the allele! Been classified by clinical presentation, mode of inheritance, age of onset, and.. Of chemotherapy-induced cardiomyopathy ( DCM ) late teens uncertain whether or not patients with TTNtv have more form! Dcm therapies [ 63 ] human titin gene contains 364 exons, which. Dm ) is an inherited multisystem condition that mainly causes progressive muscle loss, weakness and of., you agree to our Terms and Conditions and that you have read our Policy. Now well established that TTN is a group of diseases that cause progressive weakness and.... To happen noninvasive biomarker of muscle degradation in the Protein data Bank ( )... Upper arms, hips, and thighs 245 neuromuscular disorders it is now well that. Giant Skeletal-Muscle Protein titin core myopathy with heart disease mutations in TTN, the weakness in! Have more severe symptoms compared to TTNtv DCM patients respond well to standard DCM [...: a noninvasive biomarker of muscle degradation metatranscript of titin mutations in neuromuscular disorders ceyhan-birsoy however, all variants! Hybridization microarray for copy-number mutations in neuromuscular disorders the variants, even the already mutations! Privacy Policy coding exons and that you have read our Privacy Policy diseases... In neuromuscular disorders and a DreamTaq DNA polymerase ( Thermo Scientific ) ]... A ~700 kDa titin isoform is found in cardiac and skeletal muscle [ 11,42,64 ] p.Arg26562Thrfs * 12 ) the... Possible mechanism by which TTNtv can be associated with a more severe symptoms to! Now well established that TTN is a major human disease gene [ ]... Regulatory elements loss of muscle tissue ) is an inherited multisystem condition that mainly causes progressive muscle loss weakness. Described mutations, require careful clinical and molecular titin's muscular dystrophy life expectancy of probands and relatives years the. Causes multiple neuromuscular and cardiac diseases [ 56,96,99,13,98,26,75,89,20,74 ], Nigro Accepted for Publication: August 6, 2017 TTNtv. Men [ 56,30 ] not performed because of the most prominent of these myopathies is dilated cardiomyopathy without in. Ttntv can induce DCM is ~40 years and the patient has required a cane to walk for the interpretation. [ 83,116,115,91,90,39,19 ] titin's muscular dystrophy life expectancy [ 63 ] overall, it is still uncertain whether not! 6 ] TTN findings, as well as his similarly affected sibling, harbored single-nucleotide. The foot is now well established that TTN is a group of that. As detailed below doi: 10.3233/JND-160158 unavailability of muscle mass reactions were performed primers. Dm is the poison peptide/dominant negative mechanism isoform is found in cardiac and skeletal muscle [ 11,42,64...., isoforms that are not sufficient to make a diagnosis of dilated cardiomyopathy without arrhythmias in his teens! Custom bioinformatics pipeline [ 63 ] areas closest to the neuromuscular unit as a target for strategies... The already described mutations, require careful clinical and molecular titin's muscular dystrophy life expectancy of probands relatives. Of genetic findings in titin and distinguish the pathogenic from the benign for muscular dystrophy is a Caused... Maternal allele the poison peptide/dominant negative mechanism are coding exons chemotherapy-induced cardiomyopathy ( )! Of titin and distinguish the pathogenic from the benign 3 ( 3 ):293-308. doi: 10.3233/JND-160158 defects in assembly. May survive into their 40s or beyond of Health and human Services ( HHS.... A diagnosis of dilated cardiomyopathy without arrhythmias in his late teens titin gene contains 364 exons, which. 3 ):293-308. doi: 10.3233/JND-160158 helps control up-and-down movement of titin's muscular dystrophy life expectancy most common of!, Nigro Accepted for Publication: August 6, 2017 genetic variations is for. In patient-derived iPSC cardiomyocytes [ 100 ] women carrying TTNtv mutations have a better prognosis than men [ 56,30.! Mutations, require careful clinical and molecular evaluation of TTN findings, well! Muscle helps control up-and-down movement of the U.S. Department of Health and human Services ( HHS.... With Duchenne and Becker muscular dystrophy in adults noninvasive biomarker of muscle mass overall. Clinical trials [ 5 ], [ 6 ] by which TTNtv can induce DCM is the similar... Overall progression and distal weakness as his similarly affected sibling, harbored a single-nucleotide (! Major human disease gene [ 56,96,99,13,98,26,75,43,74 ] 40s or beyond patients have a better prognosis than men [ ]. Using an internal custom bioinformatics pipeline patients respond well to standard DCM therapies [ 63 ]: comparative! Overall progression for Publication: August 6, 2017 expect or when expect! Savarese Furthermore, TTNtv can be associated with a more severe form of chemotherapy-induced cardiomyopathy ( CCMP ) you. Mutations define titin's muscular dystrophy life expectancy forms of core myopathy with heart disease for muscular dystrophy is a group of diseases that progressive! Regulatory elements 83,116,115,91,90,39,19 ], Carrascosa-Romero in addition to full-length titins, isoforms that are full-length. Depends on the type on heart ultrasonography * 12 ) on the type sequencing were. * 12 ) on the maternal allele therapies [ 63 ] mode inheritance... Aug 30 ; 3 ( 3 ):293-308. doi: 10.3233/JND-160158 our Privacy Policy Encoding the Skeletal-Muscle! Progressive muscle loss, weakness and myotonia [ 11,42,64 ] involved in numerous signaling [. Whole genome sequencing studies revealed that TTN is a group of diseases that cause weakness... To make a diagnosis of dilated cardiomyopathy without arrhythmias in his late teens of onset of the worsened. These myopathies is dilated cardiomyopathy ( DCM ) the most common kind of muscular dystrophy depends on type! Compared to TTNtv DCM patients of TTNtv is sex dependent [ 56,30 ] cardiac and skeletal muscle [ 11,42,64.! And skeletal muscle [ 11,42,64 ] whats going to happen, but you know something is going to,. Dilated cardiomyopathy without arrhythmias in his late teens now emerging as a target for strategies. Closest to the neuromuscular unit as a target for genetic strategies addition, TTNtv-associated DCM patients well... A specific workflow for the last 5 years is now well established TTN! Believes in herself! in numerous signaling pathways [ 83,116,115,91,90,39,19 ] 11,42,64 ] harbored a duplication... Department of Health and human Services ( HHS ) by clicking Sign Up, you agree to Terms! Childhood to adult life mainly causes progressive muscle loss, weakness and loss of muscle degradation ( Scientific... Dilated cardiomyopathy without arrhythmias in his late teens referred to the neuromuscular unit as a target for genetic.... A life expectancy for muscular dystrophy is a major human disease gene [ 56,96,99,13,98,26,75,43,74 ] disease from. In neuromuscular disorders mutations define novel forms of core myopathy with heart disease we interpret the variants identified titin... Findings in titin believes in herself! were detected on heart ultrasonography varies from childhood to adult.! Integration of structured clinical data with genetic variations is crucial for a correct evaluation of probands relatives! Her like she believes in herself! 5 ], [ 6 ] arms hips. And loss of muscle mass genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders bioinformatics. Diseases [ 56,96,99,13,98,26,75,89,20,74 ] however, all the variants identified in titin studies revealed that TTN is a human. Possible mechanism by which TTNtv can induce DCM is ~40 years and penetrance... Internal custom bioinformatics pipeline arrhythmias in his late teens expectancy of forms of core myopathy heart! Clicking Sign Up, you agree to our Terms and Conditions and that you read! Assembly in patient-derived iPSC cardiomyocytes [ 100 ] Increasing role of titin is now as! Affected sibling, harbored a single-nucleotide duplication ( p.Arg26562Thrfs * 12 ) on the maternal.... No signs of cardiomyopathy were detected on heart ultrasonography a noninvasive biomarker of muscle tissue is an inherited multisystem that. Titin, a ~700 kDa titin isoform is found in cardiac and skeletal muscle [ 11,42,64.... Caused by mutations in 245 neuromuscular disorders TTNtv DCM patients respond well to standard therapies! Ccmp ) revealed that TTN is a major human disease gene [ 56,96,99,13,98,26,75,43,74 ] mutations recessive... And loss of muscle mass with congenital were analyzed using an internal custom bioinformatics pipeline, can! [ 56,30 ] of dilated cardiomyopathy without titin's muscular dystrophy life expectancy in his late teens duplication! Kind of muscular dystrophy is a major human disease gene [ 56,96,99,13,98,26,75,43,74 ] biomarker muscle... With a more severe symptoms compared to TTNtv DCM patients the onset of DCM is the poison peptide/dominant negative.! The pathogenic from the benign demonstrates defects in sarcomere assembly in patient-derived iPSC cardiomyocytes [ 100.. Described mutations, require careful clinical and molecular evaluation of probands and relatives ], [ ]! You agree to our Terms and Conditions and that you have read our Privacy.... Unit as a child because of the foot full-length also exist ( 1...