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Gene Review

TTN  -  titin

Homo sapiens

Synonyms: CMD1G, CMH9, CMPD4, Connectin, EOMFC, ...
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Disease relevance of TTN


Psychiatry related information on TTN


High impact information on TTN

  • 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 [11].
  • Troponin and tropomyosin isoforms determine the variable sensitivity to calcium, whereas titin isoforms dictate the elastic properties of muscle fibers at rest [11].
  • Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy [12].
  • In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc-I-band transition zone [12].
  • Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments [13].

Chemical compound and disease context of TTN


Biological context of TTN

  • Interestingly, these altered gait parameters were completely corrected by CAPN3 overexpression in transgenic C3Tg;+/mdm mice, supporting a CAPN3-dependent role for the N2A domain of TTN in the dynamics of muscle contraction [2].
  • 3. The genomic orientation of the nebulin gene was determined as 5'-3' and of TTN as 3'-5' from the centromere [3].
  • FISH in metaphases of approximately 500 bands localized NEB to 2q24.1-q24.2, while HOXD and TTN were localized to 2q31 [18].
  • Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin [19].
  • Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype [19].

Anatomical context of TTN

  • We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD [19].
  • The giant protein titin serves a primary role as a scaffold for sarcomere assembly; however, proteins that mediate this remodeling have not been identified [20].
  • Titin distribution was normal in longitudinal sections from the C3KO mice; however, EM of muscle fibers showed misaligned A-bands [20].
  • At a later maturational stage, prior to the development of cross-striated myofibrils, the IF-associated titin aggregates were found in close association with subsarcolemmally located SFLS [21].
  • The first indications of titin expression were found in postmitotic mononuclear myoblasts where it is located in a random, punctate fashion [21].

Associations of TTN with chemical compounds

  • Moreover, PK-11195 delayed the [Ca2+]i rise induced by TTN but did not significantly affect its extent, and had no effect on the [Ca2+]i rise induced by ENP [22].
  • TTN induced neutrophil chemotaxis, stimulated O2- generation, and enhanced phagocytosis [22].
  • Because neutrophils express benzodiazepine receptors of the peripheral type (pBRs) and DBI-derived peptides may interact with such receptors, we investigated the possible role of pBRs in TTN- or ENP-induced effects [22].
  • Here we present the crystal structure of titin's only catalytic domain, an autoregulated serine kinase (titin kinase) [23].
  • We describe a dual mechanism of activation of titin kinase that consists of phosphorylation of this tyrosine and binding of calcium/calmodulin to the regulatory tail [23].

Physical interactions of TTN

  • Through yeast two-hybrid experiments, calpain 3 has been shown to bind to titin in myofibrils [Sorimachi et al. (1995) J. Biol. Chem. 270, 31158-31162] [24].
  • We show that titin ZIg1/2 could form a three-way complex with sAnk1 and T-cap [25].
  • The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin [25].
  • In the central Z-disk, titin can interact with multiple alpha-actinin molecules via their C-terminal domains [26].
  • The alpha-actinin-2 binding site of the Z-disc titin is located within a sequence of 45-residue repeats, referred to as Z-repeat region [27].

Enzymatic interactions of TTN


Regulatory relationships of TTN

  • Myomesin phosphorylation at this site by cAMP-dependent kinase and similar or identical activities in muscle extracts block the association with titin [28].
  • At the Z line, titin may determine the minimum extent and tropomyosin the maximum extent of thin filament overlap by regulating alpha-actinin binding to actin, while a unique Z filament may bind to capZ and regulate barbed end capping [29].
  • Hence, not only the telethonin transcript is rapidly downregulated in denervated muscle but the protein itself undergoes dynamic changes while its known sarcomeric binding partner titin remains unaltered [30].
  • Modeling AFM-induced PEVK extension and the reversible unfolding of Ig/FNIII domains in single and multiple titin molecules [31].

Other interactions of TTN

  • The affinity for a type II peptide, 12 residues long, spanning the sequence of a stretch of titin known to colocalise with nebulin in the Z-disk is in the submicromolar range (0.7 microM) [32].
  • Within the myofibril, MARPs, myopalladin, and the calpain protease p94 appear to be components of a titin N2A-based signaling complex [33].
  • Loss of the contractile machinery and related proteins such as titin and alpha-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components [34].
  • Thereafter a more periodic localization of titin, MHC, alpha-actin and alpha-actinin on SFLS became obvious [21].
  • Titin mutations as the molecular basis for dilated cardiomyopathy [35].

Analytical, diagnostic and therapeutic context of TTN


  1. 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]
  2. Mdm muscular dystrophy: interactions with calpain 3 and a novel functional role for titin's N2A domain. Huebsch, K.A., Kudryashova, E., Wooley, C.M., Sher, R.B., Seburn, K.L., Spencer, M.J., Cox, G.A. Hum. Mol. Genet. (2005) [Pubmed]
  3. Refined localisation of the genes for nebulin and titin on chromosome 2q allows the assignment of nebulin as a candidate gene for autosomal recessive nemaline myopathy. Pelin, K., Ridanpää, M., Donner, K., Wilton, S., Krishnarajah, J., Laing, N., Kolmerer, B., Millevoi, S., Labeit, S., de la Chapelle, A., Wallgren-Petterson, C. Eur. J. Hum. Genet. (1997) [Pubmed]
  4. Skeletal muscle-specific calpain, p94, and connectin/titin: their physiological functions and relationship to limb-girdle muscular dystrophy type 2A. Sorimachi, H., Ono, Y., Suzuki, K. Adv. Exp. Med. Biol. (2000) [Pubmed]
  5. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Carmignac, V., Salih, M.A., Quijano-Roy, S., Marchand, S., Al Rayess, M.M., Mukhtar, M.M., Urtizberea, J.A., Labeit, S., Guicheney, P., Leturcq, F., Gautel, M., Fardeau, M., Campbell, K.P., Richard, I., Estournet, B., Ferreiro, A. Ann. Neurol. (2007) [Pubmed]
  6. Titin: properties and family relationships. Tskhovrebova, L., Trinick, J. Nat. Rev. Mol. Cell Biol. (2003) [Pubmed]
  7. Differential treatment responses of TMD patients as a function of psychological characteristics. Rudy, T.E., Turk, D.C., Kubinski, J.A., Zaki, H.S. Pain (1995) [Pubmed]
  8. Translating the research diagnostic criteria for temporomandibular disorders into German: evaluation of content and process. John, M.T., Hirsch, C., Reiber, T., Dworkin, S. Journal of orofacial pain. (2006) [Pubmed]
  9. Appropriate use of predictive values in clinical decision making and evaluating diagnostic tests for TMD. Levitt, S.R., McKinney, M.W. Journal of orofacial pain. (1994) [Pubmed]
  10. Prevalence of post-traumatic stress disorder symptoms in orofacial pain patients. De Leeuw, R., Bertoli, E., Schmidt, J.E., Carlson, C.R. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. (2005) [Pubmed]
  11. Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Schiaffino, S., Reggiani, C. Physiol. Rev. (1996) [Pubmed]
  12. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Gerull, B., Gramlich, M., Atherton, J., McNabb, M., Trombitás, K., Sasse-Klaassen, S., Seidman, J.G., Seidman, C., Granzier, H., Labeit, S., Frenneaux, M., Thierfelder, L. Nat. Genet. (2002) [Pubmed]
  13. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Watkins, H., Conner, D., Thierfelder, L., Jarcho, J.A., MacRae, C., McKenna, W.J., Maron, B.J., Seidman, J.G., Seidman, C.E. Nat. Genet. (1995) [Pubmed]
  14. Expression of neurofilaments and of a titin epitope in thymic epithelial tumors. Implications for the pathogenesis of myasthenia gravis. Marx, A., Wilisch, A., Schultz, A., Greiner, A., Magi, B., Pallini, V., Schalke, B., Toyka, K., Nix, W., Kirchner, T., Müller-Hermelink, H.K. Am. J. Pathol. (1996) [Pubmed]
  15. Occlusion, Orthodontic treatment, and temporomandibular disorders: a review. McNamara, J.A., Seligman, D.A., Okeson, J.P. Journal of orofacial pain. (1995) [Pubmed]
  16. Is use of exogenous estrogen associated with temporomandibular signs and symptoms? Hatch, J.P., Rugh, J.D., Sakai, S., Saunders, M.J. Journal of the American Dental Association (1939) (2001) [Pubmed]
  17. Usefulness of posture training for patients with temporomandibular disorders. Wright, E.F., Domenech, M.A., Fischer, J.R. Journal of the American Dental Association (1939) (2000) [Pubmed]
  18. Order of six loci at 2q24-q31 and orientation of the HOXD locus. Rossi, E., Faiella, A., Zeviani, M., Labeit, S., Floridia, G., Brunelli, S., Cammarata, M., Boncinelli, E., Zuffardi, O. Genomics (1994) [Pubmed]
  19. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Hackman, P., Vihola, A., Haravuori, H., Marchand, S., Sarparanta, J., De Seze, J., Labeit, S., Witt, C., Peltonen, L., Richard, I., Udd, B. Am. J. Hum. Genet. (2002) [Pubmed]
  20. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Kramerova, I., Kudryashova, E., Tidball, J.G., Spencer, M.J. Hum. Mol. Genet. (2004) [Pubmed]
  21. Titin aggregates associated with intermediate filaments align along stress fiber-like structures during human skeletal muscle cell differentiation. van der Ven, P.F., Schaart, G., Croes, H.J., Jap, P.H., Ginsel, L.A., Ramaekers, F.C. J. Cell. Sci. (1993) [Pubmed]
  22. Diazepam-binding inhibitor-derived peptides induce intracellular calcium changes and modulate human neutrophil function. Cosentino, M., Marino, F., Cattaneo, S., Di Grazia, L., Francioli, C., Fietta, A.M., Lecchini, S., Frigo, G. J. Leukoc. Biol. (2000) [Pubmed]
  23. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Mayans, O., van der Ven, P.F., Wilm, M., Mues, A., Young, P., Fürst, D.O., Wilmanns, M., Gautel, M. Nature (1998) [Pubmed]
  24. Localization of calpain 3 in human skeletal muscle and its alteration in limb-girdle muscular dystrophy 2A muscle. Keira, Y., Noguchi, S., Minami, N., Hayashi, Y.K., Nishino, I. J. Biochem. (2003) [Pubmed]
  25. The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin. Kontrogianni-Konstantopoulos, A., Bloch, R.J. J. Biol. Chem. (2003) [Pubmed]
  26. Molecular structure of the sarcomeric Z-disk: two types of titin interactions lead to an asymmetrical sorting of alpha-actinin. Young, P., Ferguson, C., Bañuelos, S., Gautel, M. EMBO J. (1998) [Pubmed]
  27. Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. Sorimachi, H., Freiburg, A., Kolmerer, B., Ishiura, S., Stier, G., Gregorio, C.C., Labeit, D., Linke, W.A., Suzuki, K., Labeit, S. J. Mol. Biol. (1997) [Pubmed]
  28. Molecular structure of the sarcomeric M band: mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin. Obermann, W.M., Gautel, M., Weber, K., Fürst, D.O. EMBO J. (1997) [Pubmed]
  29. Defining actin filament length in striated muscle: rulers and caps or dynamic stability? Littlefield, R., Fowler, V.M. Annu. Rev. Cell Dev. Biol. (1998) [Pubmed]
  30. Early and selective disappearance of telethonin protein from the sarcomere in neurogenic atrophy. Schröder, R., Reimann, J., Iakovenko, A., Mues, A., Bönnemann, C.G., Matten, J., Gautel, M. J. Muscle Res. Cell. Motil. (2001) [Pubmed]
  31. Modeling AFM-induced PEVK extension and the reversible unfolding of Ig/FNIII domains in single and multiple titin molecules. Zhang, B., Evans, J.S. Biophys. J. (2001) [Pubmed]
  32. The SH3 domain of nebulin binds selectively to type II peptides: theoretical prediction and experimental validation. Politou, A.S., Spadaccini, R., Joseph, C., Brannetti, B., Guerrini, R., Helmer-Citterich, M., Salvadori, S., Temussi, P.A., Pastore, A. J. Mol. Biol. (2002) [Pubmed]
  33. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. Miller, M.K., Bang, M.L., Witt, C.C., Labeit, D., Trombitas, C., Watanabe, K., Granzier, H., McElhinny, A.S., Gregorio, C.C., Labeit, S. J. Mol. Biol. (2003) [Pubmed]
  34. The cytoskeleton and related proteins in the human failing heart. Kostin, S., Hein, S., Arnon, E., Scholz, D., Schaper, J. Heart failure reviews. (2000) [Pubmed]
  35. Titin mutations as the molecular basis for dilated cardiomyopathy. Itoh-Satoh, M., Hayashi, T., Nishi, H., Koga, Y., Arimura, T., Koyanagi, T., Takahashi, M., Hohda, S., Ueda, K., Nouchi, T., Hiroe, M., Marumo, F., Imaizumi, T., Yasunami, M., Kimura, A. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  36. Interaction of nebulin SH3 domain with titin PEVK and myopalladin: implications for the signaling and assembly role of titin and nebulin. Ma, K., Wang, K. FEBS Lett. (2002) [Pubmed]
  37. Reverse engineering of the giant muscle protein titin. Li, H., Linke, W.A., Oberhauser, A.F., Carrion-Vazquez, M., Kerkvliet, J.G., Lu, H., Marszalek, P.E., Fernandez, J.M. Nature (2002) [Pubmed]
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