TERC

The TERC gene provides instructions for making one component of an enzyme called telomerase. Telomerase maintains structures called telomeres, which are 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 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 TERC gene is known as hTR. hTR is an RNA molecule, a chemical cousin of DNA. It provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The other major component of telomerase, which is produced from a gene called TERT, is known as hTERT. hTERT is responsible for adding the new DNA segment to chromosome ends.

dyskeratosis congenita - caused by mutations in the TERC gene

At least 11 mutations in the TERC 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, which occurs when the bone marrow does not produce enough new blood cells.

Some of the TERC mutations that cause dyskeratosis congenita result in an absent or unstable hTR molecule; others change the way hTR interacts with hTERT or other proteins in the telomerase complex.

TERC gene mutations lead to dysfunction of the telomerase complex, 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.

idiopathic pulmonary fibrosis - increased risk from variations of the TERC gene

Several mutations in the TERC gene have been identified in people with the progressive lung disease idiopathic pulmonary fibrosis. Mutations in this gene have been found in cases that run in families (familial pulmonary fibrosis) and, less commonly, in isolated (sporadic) cases.

Mutations in the TERC 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. However, researchers are unsure 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 TERC gene mutations have also been exposed to environmental risk factors, such as cigarette smoke or certain kinds of dust or fumes. It is likely that mutations in the TERC gene increase a person's risk of developing idiopathic pulmonary fibrosis, and then exposure to certain environmental factors triggers the disease.

other disorders - caused by mutations in the TERC gene

TERC 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. Researchers suggest that mutations affecting different parts of the telomerase complex may account for the absence of these features. Some believe that isolated aplastic anemia caused by TERC 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.