Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy

Article metrics


Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20–30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner–nuclear membrane proteins1. We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity2. In a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. 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. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: TTN mutation in DCM kindred A1.
Figure 2: TTN mutation in DCM kindred MAO.
Figure 3: Modular structure of the titin filament (adapted from ref. 2).

Accession codes




  1. 1

    Seidman, J.G. & Seidman, C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell 104, 557–567 (2001).

  2. 2

    Gregorio, C.C., Granzier, H., Sorimachi, H. & Labeit, S. Muscle assembly: a titanic achievement? Curr. Opin. Cell Biol. 11, 18–25 (1999).

  3. 3

    Siu, B.L. et al. Familial dilated cardiomyopathy locus maps to chromosome 2q31. Circulation 99, 1022–1026 (1999).

  4. 4

    Labeit, S. & Kolmerer, B. Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270, 293–296 (1995).

  5. 5

    Trinick, J. & Tskhovrebova, L. Titin: a molecular control freak. Trends Cell Biol. 9, 377–380 (1999).

  6. 6

    Bang, M.L. 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. Circ. Res. 89, 1065–1072.

  7. 7

    Granzier, H., Helmes, M. & Trombitas, K. Nonuniform elasticity of titin in cardiac myocytes: a study using immunoelectron microscopy and cellular mechanics. Biophys. J. 70, 430–442 (1996).

  8. 8

    Freiburg, A. et al. Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity. Circ. Res. 86, 1114–1121 (2000).

  9. 9

    Cazorla, O. et al. Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ. Res. 86, 59–67 (2000).

  10. 10

    Centner, T. et al. Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. J. Mol. Biol. 306, 717–726 (2001).

  11. 11

    Sorimachi, H. et al. Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. J. Biol. Chem. 270, 31158–31162 (1995).

  12. 12

    Takahashi, K., Hattori, A., Tatsumi, R. & Takai, K. Calcium-induced splitting of connectin filaments into beta-connectin and a 1,200-kDa subfragment. J. Biochem. 111, 778–782 (1992).

  13. 13

    Halaby, D.M., Poupon, A. & Mornon, J. The immunoglobulin fold family: sequence analysis and 3D structure comparisons. Protein Eng. 12, 563–571 (1999).

  14. 14

    Sorimachi, H. et al. Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. J. Mol. Biol. 270, 688–695 (1997).

  15. 15

    Satoh, M. et al. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem. Biophys. Res. Commun. 262, 411–417 (1999).

  16. 16

    MacRae, C.A. Genetics and dilated cardiomyopathy: limitations of candidate gene strategies. Eur. Heart J. 21, 1817–1819 (2000).

  17. 17

    Hutchison, C.J., Alvarez-Reyes, M. & Vaughan, O.A. Lamins in disease: why do ubiquitously expressed nuclear envelope proteins give rise to tissue-specific disease phenotypes? J. Cell Sci. 114, 9–19 (2001).

  18. 18

    Xu, X. et al. Cardiomyopathy in zebrafish due to mutation in a cardiac-specific exon of titin. Nature Genet. 30,10.1038/ng816 (2002).

  19. 19

    Mestroni, L. et al. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur. Heart J. 20, 9–102 (1999).

Download references


We are grateful to the families and their referring physicians. We thank R. Kühn, C. Witt, K. Rohde, L. Fitzpatrick, S. Milan and J. Müller for technical assistance. This work was supported by grants from Deutsche Herzstiftung e.V. (L.T.), Deutsche Forschungsgemeinschaft (S.L.) and from the National Institutes of Health (H.G.). The continued support of L.T. by R. Dietz (Charité, Humboldt University, Berlin) is greatly appreciated.

Author information

Correspondence to Ludwig Thierfelder.

Rights and permissions

Reprints and Permissions

About this article

Further reading