The TERT gene provides instructions for making one component of an enzyme called telomerase. Telomerase maintains structures called telomeres, which are composed of repeated segments of DNA found at the ends of chromosomes. Telomeres protect chromosomes from abnormally sticking together or breaking down (degrading). In most cells, telomeres become progressively shorter as the cell divides. After a certain number of cell divisions, the telomeres become so short that they trigger the cell to stop dividing or to self-destruct (undergo apoptosis). Telomerase counteracts the shortening of telomeres by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides.
In most types of cells, telomerase is either undetectable or active at very low levels. However, telomerase is highly active in cells that divide rapidly, such as cells that line the lungs and gastrointestinal tract, cells in bone marrow, and cells of the developing fetus. Telomerase allows these cells to divide many times without becoming damaged or undergoing apoptosis. Telomerase is also abnormally active in most cancer cells, which grow and divide without control or order.
The telomerase enzyme consists of two major components that work together. The component produced from the TERT gene is known as hTERT. The other component is produced from a gene called TERC and is known as hTR. The hTR component provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The hTERT component then adds the new DNA segment to chromosome ends.
Health Conditions Related to Genetic Changes
At least 40 mutations in the TERT gene have been identified in people with dyskeratosis congenita. This disorder is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.
Most of the TERT gene mutations that cause dyskeratosis congenita change single protein building blocks (amino acids) in the hTERT protein, causing it to be unstable or dysfunctional. The mutations interfere with telomerase function, leading to impaired maintenance of telomeres and reduced telomere length. Cells that divide rapidly are especially vulnerable to the effects of shortened telomeres. As a result, people with dyskeratosis congenita may experience a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (oral mucosa), and bone marrow.
Breakage and instability of chromosomes resulting from inadequate telomere maintenance may lead to genetic changes that allow cells to divide in an uncontrolled way, resulting in the development of cancer in some people with dyskeratosis congenita.More About This Health Condition
Idiopathic pulmonary fibrosis
At least 70 mutations in the TERT gene have been identified in people with the progressive lung disease idiopathic pulmonary fibrosis. This condition causes scar tissue (fibrosis) to build up in the lungs, which makes the lungs unable to transport oxygen into the bloodstream effectively. Mutations in the TERT gene have been found in cases that run in families (familial pulmonary fibrosis) and, less commonly, in isolated (sporadic) cases. Some individuals with idiopathic pulmonary fibrosis due to TERT gene mutations have family members with other features of dyskeratosis congenita (described above), such as aplastic anemia or cancer.
Mutations in the TERT gene reduce or eliminate the function of telomerase, which allows telomeres to become abnormally short as cells divide. The shortened telomeres likely trigger cells that divide rapidly, such as cells that line the inside of the lungs, to stop dividing or to die prematurely. In people with idiopathic pulmonary fibrosis, shorter telomeres are associated with a more severe disease and a quicker decline in lung function. Additional research is needed to confirm how shortened telomeres contribute to the progressive scarring and lung damage characteristic of idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis is a complex disease that is probably caused by a combination of genetic and environmental factors. Studies suggest that many affected people with TERT gene mutations may have also been exposed to environmental risk factors, such as cigarette smoke or certain kinds of dust or fumes. It is possible that mutations in the TERT gene increase a person's risk of developing idiopathic pulmonary fibrosis, and then exposure to certain environmental factors can trigger the disease.More About This Health Condition
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Mutations in the TERT gene have been associated with an increased risk of a type of skin cancer called melanoma. Researchers suggest that these mutations may impair telomere maintenance and result in DNA damage. Damage to genes that help control the growth and development of cells can cause uncontrolled cell growth and lead to development of cancer.More About This Health Condition
Mutations in the TERT gene have also been associated with an increased risk of a form of blood cancer called acute myeloid leukemia. As in melanoma (described above), researchers think changes in the TERT gene may impair telomere maintenance, which leads to DNA damage. Damage to genes that help control the growth and development of blood cells can cause uncontrolled cell growth and promote the development of leukemia.
TERT gene mutations have also been found in people with isolated aplastic anemia, a form of bone marrow failure that occurs without the other physical features of dyskeratosis congenita (described above). Researchers suggest that mutations affecting different parts of the telomerase enzyme may account for the absence of these features. Some believe that isolated aplastic anemia caused by TERT gene mutations may actually represent a late-onset form of dyskeratosis congenita in which physical features such as nail dystrophy are mild and may not be noticeable.
Other Names for This Gene
- telomerase catalytic subunit
- telomerase-associated protein 2
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
- Arish N, Petukhov D, Wallach-Dayan SB. The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications. Int J Mol Sci. 2019 Jun 19;20(12):2996. doi: 10.3390/ijms20122996. Citation on PubMed or Free article on PubMed Central
- Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960-4. doi: 10.1073/pnas.0508124102. Epub 2005 Oct 24. Citation on PubMed or Free article on PubMed Central
- Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007 Mar 29;356(13):1317-26. doi: 10.1056/NEJMoa066157. Citation on PubMed
- Autexier C, Lue NF. The structure and function of telomerase reverse transcriptase. Annu Rev Biochem. 2006;75:493-517. doi: 10.1146/annurev.biochem.75.103004.142412. Citation on PubMed
- Baird DM. Variation at the TERT locus and predisposition for cancer. Expert Rev Mol Med. 2010 May 18;12:e16. doi: 10.1017/S146239941000147X. Citation on PubMed
- Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2013 Jun;6(3):327-37. doi: 10.1586/ehm.13.23. Citation on PubMed
- Basel-Vanagaite L, Dokal I, Tamary H, Avigdor A, Garty BZ, Volkov A, Vulliamy T. Expanding the clinical phenotype of autosomal dominant dyskeratosis congenita caused by TERT mutations. Haematologica. 2008 Jun;93(6):943-4. doi: 10.3324/haematol.12317. Epub 2008 May 6. No abstract available. Citation on PubMed
- Cao Y, Bryan TM, Reddel RR. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci. 2008 Jun;99(6):1092-9. doi: 10.1111/j.1349-7006.2008.00815.x. Citation on PubMed
- Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013 Feb 22;339(6122):957-9. doi: 10.1126/science.1229259. Epub 2013 Jan 24. Citation on PubMed or Free article on PubMed Central
- Marrone A, Walne A, Tamary H, Masunari Y, Kirwan M, Beswick R, Vulliamy T, Dokal I. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood. 2007 Dec 15;110(13):4198-205. doi: 10.1182/blood-2006-12-062851. Epub 2007 Sep 4. Citation on PubMed or Free article on PubMed Central
- Nishio N, Kojima S. Recent progress in dyskeratosis congenita. Int J Hematol. 2010 Oct;92(3):419-24. doi: 10.1007/s12185-010-0695-5. Epub 2010 Oct 1. Citation on PubMed
- Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552-7. doi: 10.1073/pnas.0701009104. Epub 2007 Apr 25. Citation on PubMed or Free article on PubMed Central
- Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005 May-Jun;34(3):257-63. doi: 10.1016/j.bcmd.2004.12.008. Citation on PubMed
- Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005 Apr 7;352(14):1413-24. doi: 10.1056/NEJMoa042980. Citation on PubMed
- Yan S, Han B, Wu Y, Zhou D, Zhao Y. Telomerase gene mutation screening and telomere overhang detection in Chinese patients with acute myeloid leukemia. Leuk Lymphoma. 2013 Jul;54(7):1437-41. doi: 10.3109/10428194.2012.729834. Epub 2012 Dec 10. Citation on PubMed