Telomeres and diseases (2)
Telomeropathy
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Congenital dyskeratosisViolation of telomere repair mechanisms can be caused by mutations that significantly reduce the ability of telomerase to lengthen telomeres, which leads to accelerated destruction of chromosomes [9].
The classic "telomere disease" is congenital dyskeratosis, a rare hereditary disease characterized by defective bone marrow function. A hereditary defect in the DKC1 gene in X-linked congenital dyskeratosis was identified by Inderjeet Dokal when analyzing coupling groups in a large number of people with a family history of the disease [10]. The DKC1 gene encodes dyskeratin– a protein that binds to the RNA component of telomerase and stabilizes the telomerase complex. Heterozygous TERC mutations were later detected in representatives of some families with autosomal dominant congenital dyskeratosis [11]. The severe phenotype of X-linked congenital dyskeratosis is most likely due to hemizygous loss of DKC1 and significantly reduced efficiency of telomerase functioning. In autosomal dominant congenital dyskeratosis caused by defects in TERC and other somatic chromosome genes, telomerase function is impaired due to the inferiority of a gene on one of the paired chromosomes, which reduces the level of the protein product of the gene.
Congenital dyskeratosis has pathognomonic (certainly characteristic of this disease) signs. Historically, the disease was first described by dermatologists, to whom patients often turn to this day about abnormal nail changes and pigmented mesh rash. The final component of this diagnostic triad is leukoplakia (keratinization) of the oral mucosa. In such patients, in the first decade of life, as a rule, aplastic anemia develops (suppression of the hematopoietic function of the bone marrow). With congenital dyskeratosis, the lungs and liver also function imperfectly or lose the ability to function normally after stem cell transplantation carried out to treat bone marrow disease.
Adult telomeropathyCongenital dyskeratosis and its typical manifestations in some cases may occur in adults, for example, in patients with the DKC1 mutation, whose leukocyte count does not recover after chemotherapy.
However, most adult telomeropathies are the result of mutations of TERC and the enzymatic component encoded by TERT, which do not lead to the inevitable development of the disease, but rather are risk factors. The first TERT mutations detected in humans were found in patients with acquired aplastic anemia who did not have physical abnormalities and a corresponding family history. The formation of phenotypic signs of TERT and TERC mutations at the level of the whole organism is characterized by high variability both within families and between them, which is manifested by significant differences in the severity of the course, the age at which the first symptoms appear, and the involvement of organs. Within the same families, relatives with the mutation may have no or minimal clinical manifestations at all, at later stages of life they may develop aplastic anemia, pulmonary fibrosis or liver cirrhosis [9]. Telomerase mutations were detected in a significant proportion of patients with a family history of pulmonary fibrosis, as well as in populations of patients with severe cirrhosis of the liver.
In hematopoietic stem cells, telomerase activity is increased to ensure a constant supply of erythrocytes, leukocytes and platelets to the blood; violations of hematopoietic function in telomeropathies are caused by a decrease in the number of bone marrow stem cells and their ability to recover. However, the problems that telomeropathies cause in the liver and especially in the lungs are much more difficult to explain, since the need for proliferation of their cells is considered low, and the types of cells involved in the damage are unknown. At the same time, in elderly patients, the skin and mucous membranes are rarely damaged, and the intestines, oddly enough, do not suffer at all from congenital dyskeratosis or other telomeric diseases: patients do not develop inflammatory lesions of the mucous membranes and retain the ability to absorb, despite the fact that for both types of tissues high levels of cell replication are characteristic. The mechanisms underlying the diseases caused by telomeropathies are practically unknown. It is unclear why fibrosis develops in the lungs and liver, whereas in aplastic anemia, the bone marrow is replaced by adipose tissue. The contribution of environmental factors to the development of telomeropathy is also unknown (attacks of the immune system on the bone marrow in aplastic anemia, smoking in lung damage, as well as alcohol and viral infections in liver damage).
Clinical significanceThe relationship between telomerase mutations and diseases of three different organ systems (blood, lungs and liver) is of great practical importance for patients and doctors.
In the presence of a family history, even small deviations in the quantitative parameters of blood cells, lung fibrosis and liver cirrhosis are important data for the diagnosis of telomeropathy (as in acute myeloid leukemia, see below), but the variety of symptoms can confuse any of the narrow specialists involved in the patient. One of the recent achievements is the appearance of commercial kits for estimating the length of telomeres in leukocytes, the strong shortening of which is a reliable diagnostic marker [12]. The sequence of the TERT and TERC genes can also be sequenced. The detection of telomerase deficiency affects the prognosis of the course and approaches to the treatment of the disease, as well as genetic counseling.
Despite the fact that the diagnosis of telomeropathy is obvious, its formulation may be associated with certain difficulties. Representatives of some families with typical symptoms have no known mutations, while in others the telomere length may be normal in the presence of etiological (such as without which the disease will never develop) nucleotide substitutions. Rare mutations of genes encoding shelterin proteins can lead to severe congenital dyskeratosis without altering the ability of telomerase to repair telomeres. In some cases, the cause may be hidden in regulatory regions of genes that are not usually screened.
Continuation: Telomere shortening and cancerPortal "Eternal youth" http://vechnayamolodost.ru