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TTN

Reviewed December 2013

What is the official name of the TTN gene?

The official name of this gene is “titin.”

TTN is the gene's official symbol. The TTN gene is also known by other names, listed below.

What is the normal function of the TTN gene?

The TTN gene provides instructions for making a very large protein called titin. This protein plays an important role in muscles the body uses for movement (skeletal muscles) and in heart (cardiac) muscle. Slightly different versions, or isoforms, of titin are made in different muscles.

Within muscle cells, titin is an essential component of structures called sarcomeres. Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of the protein's main jobs is to provide structure, flexibility, and stability to these cell structures. Titin interacts with other muscle proteins, including actin and myosin, to keep the components of sarcomeres in place as muscles contract and relax. Titin also contains a spring-like region that allows muscles to stretch. Additionally, researchers have found that titin plays a role in chemical signaling and in assembling new sarcomeres.

Does the TTN gene share characteristics with other genes?

The TTN gene belongs to a family of genes called fibronectin type III domain containing (fibronectin type III domain containing). It also belongs to a family of genes called immunoglobulin superfamily, immunoglobulin-like domain containing (immunoglobulin superfamily, immunoglobulin-like domain containing). It also belongs to a family of genes called immunoglobulin superfamily, I-set domain containing (immunoglobulin superfamily, I-set domain containing).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the TTN gene related to health conditions?

familial dilated cardiomyopathy - caused by mutations in the TTN gene

More than 40 mutations in the TTN gene have been found to cause familial dilated cardiomyopathy, a condition that weakens and enlarges the heart, preventing it from pumping blood efficiently. Signs and symptoms of familial dilated cardiomyopathy typically begin in mid-adulthood and result in heart failure. TTN gene mutations account for approximately 20 percent of all cases of familial dilated cardiomyopathy. These mutations result in the production of an abnormally short titin protein. It is unclear how the altered protein causes familial dilated cardiomyopathy, but it likely impairs sarcomere function and disrupts chemical signaling. Changes in sarcomere function reduce the heart's ability to contract, weakening and thinning cardiac muscle and leading to the signs and symptoms of familial dilated cardiomyopathy.

hereditary myopathy with early respiratory failure - caused by mutations in the TTN gene

At least one mutation in the TTN gene has been found to cause hereditary myopathy with early respiratory failure (HMERF), an inherited muscle disease that predominantly affects muscles close to the center of the body (proximal muscles) and muscles that are needed for breathing. The identified mutation changes a single protein building block (amino acid) in the titin protein. Specifically, it replaces the amino acid arginine with the amino acid tryptophan at protein position 279 (written as Arg279Trp or R279W). Studies suggest that this change disrupts titin's interactions with other proteins within sarcomeres and interferes with the protein's role in chemical signaling. Consequently, muscle fibers become damaged and weaken over time. It is unclear why these effects are usually limited to proximal muscles and muscles involved in breathing.

limb-girdle muscular dystrophy - caused by mutations in the TTN gene

At least one TTN gene mutation has been found to cause limb-girdle muscular dystrophy type 2J (LGMD2J). Limb-girdle muscular dystrophy is a group of related disorders characterized by weakness and wasting of skeletal muscles, particularly in the shoulders, hips, and limbs. LGMD2J is a type of limb-girdle muscular dystrophy that has been identified only in the Finnish population, and all affected individuals have had the same TTN gene mutation. This genetic change deletes several amino acids and replaces them with other amino acids near the end of the titin protein. This complex mutation is known as FINmaj. The FINmaj mutation may disrupt titin's interactions with other proteins that are needed for muscle contraction. Decreased ability to contract causes muscles to weaken and waste away over time, resulting in the signs and symptoms of limb-girdle muscular dystrophy.

Salih myopathy - caused by mutations in the TTN gene

At least two mutations in the TTN gene have been identified in people with Salih myopathy, an inherited muscle disease that affects both skeletal and cardiac muscle. These genetic changes occur near the end of the titin gene and lead to the production of an abnormally short version of the titin protein. The defective protein disrupts the function of sarcomeres, preventing skeletal and cardiac muscle from developing and working normally. These muscle abnormalities underlie the characteristic features of Salih myopathy, including skeletal muscle weakness and a form of heart disease called dilated cardiomyopathy.

tibial muscular dystrophy - caused by mutations in the TTN gene

Several mutations in the TTN gene have been identified in people with tibial muscular dystrophy, a condition that primarily affects the muscles at the front of the lower leg. The FINmaj mutation, described above, has been found to cause tibial muscular dystrophy in all affected people of Finnish descent. Other TTN gene mutations cause tibial muscular dystrophy in non-Finnish European populations.

Researchers predict that the TTN gene mutations responsible for tibial muscular dystrophy, including FINmaj, alter the ability of the titin protein to interact with other proteins within sarcomeres. Mutations may also interfere with the protein's role in chemical signaling. These changes disrupt normal muscle contraction, which causes muscles to weaken and waste away over time. It is unclear why these effects are usually limited to muscles in the lower legs in tibial muscular dystrophy.

other disorders - caused by mutations in the TTN gene

Mutations in the TTN gene can also cause a disorder of the cardiac muscle called familial hypertrophic cardiomyopathy type 9. Hypertrophic cardiomyopathy is a thickening of the cardiac muscle that forces the heart to work harder to pump blood. This condition is often associated with an abnormal heartbeat (arrhythmia) and can lead to heart failure and sudden death. Researchers have found at least three TTN gene mutations in people with familial hypertrophic cardiomyopathy type 9.

The mutations responsible for this heart condition likely disrupt the normal structure and function of titin. The genetic changes may alter titin's interactions with other muscle proteins or disrupt its role in chemical signaling. Researchers are working to determine why some conditions resulting from TTN gene mutations predominantly affect cardiac muscle, some predominantly affect skeletal muscle, and some affect both. They suspect that these differences may be related to the location of mutations in the TTN gene and the many varieties of titin that are produced in different muscles.

Where is the TTN gene located?

Cytogenetic Location: 2q31

Molecular Location on chromosome 2: base pairs 178,525,988 to 178,807,422

The TTN gene is located on the long (q) arm of chromosome 2 at position 31.

The TTN gene is located on the long (q) arm of chromosome 2 at position 31.

More precisely, the TTN gene is located from base pair 178,525,988 to base pair 178,807,422 on chromosome 2.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about TTN?

You and your healthcare professional may find the following resources about TTN helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the TTN gene or gene products?

  • CMH9
  • CMPD4
  • CONNECTIN
  • EOMFC
  • FLJ32040
  • LGMD2J
  • MYLK5
  • TITIN_HUMAN
  • TMD

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding TTN?

acids ; actin ; amino acid ; arginine ; arrhythmia ; cardiac ; cardiomyopathy ; cell ; contraction ; dilated ; familial ; gene ; heart failure ; hereditary ; hypertrophic ; inherited ; isoforms ; muscle cells ; muscular dystrophy ; mutation ; myosin ; population ; protein ; proximal ; respiratory ; sarcomere ; skeletal muscle ; tryptophan ; wasting

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol. 2007 Apr;61(4):340-51. Erratum in: Ann Neurol. 2012 May;71(5):728. (http://www.ncbi.nlm.nih.gov/pubmed/17444505?dopt=Abstract)
  • Fukuda N, Granzier HL, Ishiwata S, Kurihara S. Physiological functions of the giant elastic protein titin in mammalian striated muscle. J Physiol Sci. 2008 Jun;58(3):151-9. doi: 10.2170/physiolsci.RV005408. Epub 2008 May 15. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18477421?dopt=Abstract)
  • Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M. Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies. J Cell Sci. 2008 Jun 1;121(Pt 11):1841-51. doi: 10.1242/jcs.028019. Epub 2008 May 13. (http://www.ncbi.nlm.nih.gov/pubmed/18477606?dopt=Abstract)
  • Gerull B, Gramlich M, Atherton J, McNabb M, Trombitás K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002 Feb;30(2):201-4. Epub 2002 Jan 14. (http://www.ncbi.nlm.nih.gov/pubmed/11788824?dopt=Abstract)
  • Hackman JP, Vihola AK, Udd AB. The role of titin in muscular disorders. Ann Med. 2003;35(6):434-41. (http://www.ncbi.nlm.nih.gov/pubmed/14572168?dopt=Abstract)
  • Hackman P, Marchand S, Sarparanta J, Vihola A, Pénisson-Besnier I, Eymard B, Pardal-Fernández JM, Hammouda el-H, Richard I, Illa I, Udd B. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord. 2008 Dec;18(12):922-8. doi: 10.1016/j.nmd.2008.07.010. Epub 2008 Oct 22. (http://www.ncbi.nlm.nih.gov/pubmed/18948003?dopt=Abstract)
  • Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet. 2002 Sep;71(3):492-500. Epub 2002 Jul 26. (http://www.ncbi.nlm.nih.gov/pubmed/12145747?dopt=Abstract)
  • 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. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186. (http://www.ncbi.nlm.nih.gov/pubmed/22335739?dopt=Abstract)
  • 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. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186. (http://www.ncbi.nlm.nih.gov/pubmed/22335739?dopt=Abstract)
  • Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edström L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005 Jun 10;308(5728):1599-603. Epub 2005 Mar 31. (http://www.ncbi.nlm.nih.gov/pubmed/15802564?dopt=Abstract)
  • Linke WA. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res. 2008 Mar 1;77(4):637-48. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17475230?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/7273)
  • Nicolao P, Xiang F, Gunnarsson LG, Giometto B, Edström L, Anvret M, Zhang Z. Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q. Am J Hum Genet. 1999 Mar;64(3):788-92. (http://www.ncbi.nlm.nih.gov/pubmed/10053013?dopt=Abstract)
  • Norton N, Li D, Rampersaud E, Morales A, Martin ER, Zuchner S, Guo S, Gonzalez M, Hedges DJ, Robertson PD, Krumm N, Nickerson DA, Hershberger RE; National Heart, Lung, and Blood Institute GO Exome Sequencing Project and the Exome Sequencing Project Family Studies Project Team. Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Circ Cardiovasc Genet. 2013 Apr;6(2):144-53. doi: 10.1161/CIRCGENETICS.111.000062. Epub 2013 Feb 15. (http://www.ncbi.nlm.nih.gov/pubmed/23418287?dopt=Abstract)
  • Pénisson-Besnier I, Hackman P, Suominen T, Sarparanta J, Huovinen S, Richard-Crémieux I, Udd B. Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype. J Neurol Neurosurg Psychiatry. 2010 Nov;81(11):1200-2. doi: 10.1136/jnnp.2009.178434. Epub 2010 Jun 22. (http://www.ncbi.nlm.nih.gov/pubmed/20571043?dopt=Abstract)
  • Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999 Aug 27;262(2):411-7. (http://www.ncbi.nlm.nih.gov/pubmed/10462489?dopt=Abstract)
  • Tskhovrebova L, Trinick J. Titin: properties and family relationships. Nat Rev Mol Cell Biol. 2003 Sep;4(9):679-89. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14506471?dopt=Abstract)
  • Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology. 2005 Feb 22;64(4):636-42. (http://www.ncbi.nlm.nih.gov/pubmed/15728284?dopt=Abstract)
  • Udd B. Distal myopathies. Handb Clin Neurol. 2007;86:215-41. doi: 10.1016/S0072-9752(07)86011-8. (http://www.ncbi.nlm.nih.gov/pubmed/18809003?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: December 2013
Published: January 27, 2015