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Gene Review

Ttn  -  titin

Mus musculus

Synonyms: 1100001C23Rik, 2310036G12Rik, 2310057K23Rik, 2310074I15Rik, AF006999, ...
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Disease relevance of Ttn


High impact information on Ttn

  • Troponin and tropomyosin isoforms determine the variable sensitivity to calcium, whereas titin isoforms dictate the elastic properties of muscle fibers at rest [7].
  • Additional isoforms, including products of tropomyosin, myosin light chain 1 fast, troponin T, titin, and nebulin genes, can be generated from the same gene through alternative splicing or use of alternative promoters [7].
  • In this study, we use a titin M line-deficient mouse to show that the initial assembly of the sarcomere does not depend on titin's M-line region or the phosphorylation of T-cap by the titin kinase [8].
  • Even without titin integrating into the M band, sarcomeres show proper spacing and alignment of Z discs and M bands but fail to grow laterally and ultimately disassemble [8].
  • These reveal a periodic pattern of myosin, nebulin, and those titin epitopes known to occur at and close to the Z line [9].

Biological context of Ttn

  • The gene order (distances in cM) cenVim-16.9 +/- 4.7-Neb-7.6 +/- 3.0-Ttn, Acra-18.0 +/- 4.9-Pax-6-17.7 +/- 4.9-a ... has been determined [1].
  • Myogenesis in the mouse embryo: differential onset of expression of myogenic proteins and the involvement of titin in myofibril assembly [9].
  • The comparison of disassembly in the developing and mature knockout sarcomere suggests diverse functions for titin's M line in embryonic development and the adult heart that not only involve the differential expression of titin isoforms but also of titin-binding proteins [8].
  • We investigated the response to deletion of the titin M-line region in striated muscle, using a titin knockout model and a range of techniques that include histology, in situ hybridization, electron microscopy, and 2D gel analysis [3].
  • The mutant protein was designed to have a similar size as the skeletal MyBP-C isoforms, whereas known myosin and titin binding sites as well as the phosphorylatable MyBP-C motif were not altered [10].

Anatomical context of Ttn

  • Our results indicate that the putative elastic titin filaments act as integrators during skeletal muscle development [9].
  • In contrast titin epitopes, which are present in mature myofibrils along the A band and at the A-I junction, are still randomly distributed [9].
  • After fusion of myoblasts to myotubes at g.d. 13 and 14 all titin epitopes show the myofibrillar banding pattern [9].
  • This alternative spliced form of MyBP-C(+) has a markedly decreased binding affinity to myosin filaments and connectin/titin in vitro and does not localize to A-bands in cardiac myocytes [11].
  • We investigated the effects of diabetes, physical training, and their combination on the gene expression of proteins of putative titin stretch-sensing complexes in skeletal and cardiac muscle [12].

Associations of Ttn with chemical compounds

  • Another unique feature of titin is the presence of a serine/threonine kinase-like domain at the edge of the M-line region of the sarcomere, for which no physiological catalytic function has yet been shown [4].
  • Effects of streptozotocin-induced diabetes and physical training on gene expression of titin-based stretch-sensing complexes in mouse striated muscle [12].
  • The gene product, connectin, is a member of the leucine-rich repeat protein family and we show that it is attached to the cell surface via a glycosylphosphatidylinositol linkage and that it can mediate homotypic cell-cell adhesion in vitro [5].
  • Here we show by low-percentage polyacrylamide-gel electrophoresis that developmentally regulated switching of cardiac titin/connectin size occurs in the hearts of mouse, rat, pig, and chicken [13].

Physical interactions of Ttn

  • Thus, the composition of the titin N2A protein complex is altered in MDM by incorporation of CARP and loss of p94/calpain-3 [2].

Regulatory relationships of Ttn

  • To investigate the role of IGHMBP2 in the pathogenesis of DCM, we generated transgenic mice expressing the full-length Ighmbp2 cDNA specifically in myocytes under the control of the mouse titin promoter [14].
  • We tested whether titin-based passive tension influences the interfilament lattice spacing by measuring the width of the myocyte and by using small-angle x-ray diffraction of mouse left ventricular wall muscle [15].

Other interactions of Ttn

  • Passive stiffness changes in soleus muscles from desmin knockout mice are not due to titin modifications [16].
  • Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling [2].
  • In addition to the structural importance of the titin M-line region in any striated muscle, our data show how differences in M-line composition between heart and skeletal muscle affect sarcomere stability and function [3].
  • Herein, we are reporting a novel alternative spliced form of cardiac MyBP-C, MyBP-C(+), which includes an extra 30 nucleotides, encoding 10 amino acids in the carboxyl-terminal connectin/titin binding region [11].
  • One of these mutants carries a stop codon mutation in dystrophin, and we have recently identified another carrying a mutation in titin [17].

Analytical, diagnostic and therapeutic context of Ttn

  • This is the first demonstration that a mutation in Ttn is associated with muscular dystrophy and provides a novel animal model to test for functional interactions between TTN and CAPN3 [18].
  • We used a gene-targeting approach in cultured myoblasts to truncate the titin gene so that the kinase domain and other domains downstream of the kinase were not expressed [19].
  • Immunofluorescence staining of postmitotic mononuclear myoblasts indicate that the investigated epitopes of the titin molecule are displayed in a punctate pattern with neighboring, but clearly separate spots in the cytoplasm of the cells [20].
  • In this work, immunoelectron microscopy was used to study the molecular origin of the in vivo extensibility of the I-band region of cardiac titin [21].
  • This difference from wildtype controls (+/+ or +/mdm) is also reflected in the yield of mononucleate myogenic cells upon dissociation of skeletal muscle and subsequent cell culture [22].


  1. Chromosomal localization of the mouse titin gene and its relation to "muscular dystrophy with myositis" and nebulin genes on chromosome 2. Müller-Seitz, M., Kaupmann, K., Labeit, S., Jockusch, H. Genomics (1993) [Pubmed]
  2. Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling. Witt, C.C., Ono, Y., Puschmann, E., McNabb, M., Wu, Y., Gotthardt, M., Witt, S.H., Haak, M., Labeit, D., Gregorio, C.C., Sorimachi, H., Granzier, H., Labeit, S. J. Mol. Biol. (2004) [Pubmed]
  3. Muscle atrophy in Titin M-line deficient mice. Peng, J., Raddatz, K., Labeit, S., Granzier, H., Gotthardt, M. J. Muscle Res. Cell. Motil. (2005) [Pubmed]
  4. Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure. Gotthardt, M., Hammer, R.E., Hübner, N., Monti, J., Witt, C.C., McNabb, M., Richardson, J.A., Granzier, H., Labeit, S., Herz, J. J. Biol. Chem. (2003) [Pubmed]
  5. The cell adhesion molecule, connectin, and the development of the Drosophila neuromuscular system. Meadows, L.A., Gell, D., Broadie, K., Gould, A.P., White, R.A. J. Cell. Sci. (1994) [Pubmed]
  6. Multiple molecular interactions implicate the connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle. Hayashi, C., Ono, Y., Doi, N., Kitamura, F., Tagami, M., Mineki, R., Arai, T., Taguchi, H., Yanagida, M., Hirner, S., Labeit, D., Labeit, S., Sorimachi, H. J. Biol. Chem. (2008) [Pubmed]
  7. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Schiaffino, S., Reggiani, C. Physiol. Rev. (1996) [Pubmed]
  8. M line-deficient titin causes cardiac lethality through impaired maturation of the sarcomere. Weinert, S., Bergmann, N., Luo, X., Erdmann, B., Gotthardt, M. J. Cell Biol. (2006) [Pubmed]
  9. Myogenesis in the mouse embryo: differential onset of expression of myogenic proteins and the involvement of titin in myofibril assembly. Fürst, D.O., Osborn, M., Weber, K. J. Cell Biol. (1989) [Pubmed]
  10. Hypercontractile properties of cardiac muscle fibers in a knock-in mouse model of cardiac myosin-binding protein-C. Witt, C.C., Gerull, B., Davies, M.J., Centner, T., Linke, W.A., Thierfelder, L. J. Biol. Chem. (2001) [Pubmed]
  11. A novel variant of cardiac myosin-binding protein-C that is unable to assemble into sarcomeres is expressed in the aged mouse atrium. Sato, N., Kawakami, T., Nakayama, A., Suzuki, H., Kasahara, H., Obinata, T. Mol. Biol. Cell (2003) [Pubmed]
  12. Effects of streptozotocin-induced diabetes and physical training on gene expression of titin-based stretch-sensing complexes in mouse striated muscle. Lehti, T.M., Silvennoinen, M., Kivelä, R., Kainulainen, H., Komulainen, J. Am. J. Physiol. Endocrinol. Metab. (2007) [Pubmed]
  13. Plasticity of cardiac titin/connectin in heart development. Opitz, C.A., Linke, W.A. J. Muscle Res. Cell. Motil. (2005) [Pubmed]
  14. Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival. Maddatu, T.P., Garvey, S.M., Schroeder, D.G., Zhang, W., Kim, S.Y., Nicholson, A.I., Davis, C.J., Cox, G.A. Hum. Mol. Genet. (2005) [Pubmed]
  15. Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes. Cazorla, O., Wu, Y., Irving, T.C., Granzier, H. Circ. Res. (2001) [Pubmed]
  16. Passive stiffness changes in soleus muscles from desmin knockout mice are not due to titin modifications. Anderson, J., Joumaa, V., Stevens, L., Neagoe, C., Li, Z., Mounier, Y., Linke, W.A., Goubel, F. Pflugers Arch. (2002) [Pubmed]
  17. Diagnosis and cell-based therapy for Duchenne muscular dystrophy in humans, mice, and zebrafish. Kunkel, L.M., Bachrach, E., Bennett, R.R., Guyon, J., Steffen, L. J. Hum. Genet. (2006) [Pubmed]
  18. The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin. Garvey, S.M., Rajan, C., Lerner, A.P., Frankel, W.N., Cox, G.A. Genomics (2002) [Pubmed]
  19. A targeted deletion of the C-terminal end of titin, including the titin kinase domain, impairs myofibrillogenesis. Miller, G., Musa, H., Gautel, M., Peckham, M. J. Cell. Sci. (2003) [Pubmed]
  20. Integration of titin into the sarcomeres of cultured differentiating human skeletal muscle cells. van der Loop, F.T., van der Ven, P.F., Fürst, D.O., Gautel, M., van Eys, G.J., Ramaekers, F.C. Eur. J. Cell Biol. (1996) [Pubmed]
  21. Molecular dissection of N2B cardiac titin's extensibility. Trombitás, K., Freiburg, A., Centner, T., Labeit, S., Granzier, H. Biophys. J. (1999) [Pubmed]
  22. Overshooting production of satellite cells in murine skeletal muscle affected by the mutation "muscular dystrophy with myositis" (mdm, Chr 2). Heimann, P., Menke, A., Rothkegel, B., Jockusch, H. Cell Tissue Res. (1996) [Pubmed]
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