Dyskeratosis congenita types DKCA1, DKCB1, DKCA2, DKCB2, DKCA3, DKCB3, DKCA4, DKCB4, DKCA5, DKCB5, DKCX (dyskeratosis congenita types DKCA1, DKCB1, DKCA2, DKCB2, DKCA3, DKCB3, DKCA4, DKCB4, DKCA5, DKCB5, DKCX) - Genes TERT, TERC, DKC1, TINF2, Nop10, NHP2, Wrap53 and RTEL1.

Dyskeratosis congenita is a disorder that can affect many parts of the body. The three key features include nail dystrophy, pigmentation changes (especially in the neck and chest) and oral leukoplakia.

Affected individuals have an increased risk of developing various diseases that compromise life. They are especially vulnerable to diseases that alter the function of the bone marrow, or disrupting the ability of the bone marrow to produce new blood cells, so they may have aplastic anemia, when the bone marrow does not produce enough new blood cells. They are also at risk of myelodysplastic syndrome, a disorder in which immature blood cells do not develop normally. This alteration can trigger leukemia. Furthermore, people with dyskeratosis congenita have a higher average of developing other types of cancer, especially in the neck, the anus or genitals, and pulmonary fibrosis risk.

Other additional signs and symptoms include eye abnormalities such as narrow tear ducts which prevent proper drainage of tears and cause eyelid irritation, dental problems, hair loss or hair prematurely gray, osteoporosis, avascular necrosis of the hip joints and shoulder and liver disease. Some affected males may have urethral strictures, accompanied by difficulty in urination, discomfort and urinary tract infections.

The severity of the disease varies widely among affected individuals. People are less affected only some mild physical characteristics of the disease and bone marrow function is normal. Individuals affected by a severe disease have many of the physical characteristics and deficient in bone marrow, any cancer or lung fibrosis in early adulthood. While most of those affected have normal intelligence and normal development of motor skills in some people with severe presentations delayed development can occur. In an intense form of the disease known as Hoyeraal-Hreidaarsson syndrome, affected individuals have an unusually small and underdeveloped cerebellum. Another serious variant called Revesz syndrome involves abnormalities in the retina, in addition to other symptoms of dyskeratosis congenita.

In about half of people with dyskeratosis congenita, the disease is due to mutations in the DKC1 gene, TERT, TERC or TINF2. These genes encode proteins that help maintain telomeres found at the ends of chromosomes. In a small number of individuals with dyskeratosis congenita, mutations have been identified in other genes involved in telomere maintenance, such as Nop10, NHP2, Wrap53 and RTEL1 gene. Other affected persons do not have mutations in either gene currently associated with dyskeratosis congenita. In these cases, the cause of the disease is unknown. However, it is likely that other genes, hitherto unknown, related to the maintenance of telomeres are involved.

The DKC1 gene, located on the long arm of the X chromosome (Xq28), encodes a protein called dyskerin. This protein is involved in telomere maintenance. In most cells, the telomeres become progressively shorter as the cell divides. After a certain number of cell divisions, the telomeres become so short that trigger apoptosis. Telomeres are maintained by two complexes of important proteins telomerase and shelterin. Telomerase counteracts the shortening of telomeres by adding small DNA repeated segments to the ends of chromosomes each time the cell divides. One component of telomerase, known hTR, provides guidance for creating repeated DNA sequence. Dyskerin protein aggregates bind to hTR and help stabilize the telomerase complex. In most cell types, or undetectable telomerase is active at very low concentrations. However, telomerase is active in the cells that the cells in the bone marrow and cells of the developing fetus rapidly dividing, such as the cells lining the lungs and gastrointestinal tract. Telomerase is also abnormally active in most cancer cells, which grow and divide without control. The dyskerin protein is also involved in encoding ribosomal RNA (rRNA), required for assembling amino acids into functional proteins.

They have identified more than 40 mutations in the DKC1 gene in individuals with X - linked dyskeratosis congenita (DKCX). Most of these mutations in dyskerin substituted amino acid protein. It is believed that these changes probably interfere with the ability of the protein to bind hTR dyskerin, causing dysfunction of the telomerase complex. The deterioration of the function of telomerase prevents normal telomere maintenance and leads to reduced telomere length. The cells are rapidly dividing are particularly vulnerable to the effects of telomere shortening. As a result, individuals with dyskeratosis congenita can present a variety of problems that cause the cells to divide rapidly in the body. Breakage and instability of chromosomes, due to inadequate maintenance of telomeres, can cause genetic changes that allow the cells to divide uncontrollably, which leads to cancer in some people with dyskeratosis congenita.

The TERC gene, located on the long arm of chromosome 3 (3q26), and the TERT gene, located on the short arm of chromosome 5 (5p15.33), encoding telomerase components responsible for maintaining telomeres. They have identified at least 11 TERC gene mutations and 18 mutations in the gene PERT in people with dyskeratosis congenita. Mutations in the gene TERC, give rise to autosomal dominant dyskeratosis congenita 1 (DKCA1) and a severe form of dyskeratosis congenita known as Hoyeraal-Hreidaarsson syndrome. Some of the TERC gene mutations lead to the absence or instability of hTR. Other mutations change the way it interacts with hTERT or hTR other components of the telomerase enzyme. Meanwhile, mutations in the TERT gene, result in autosomal recessive dyskeratosis congenita 2 (DKCA2) and autosomal recessive dyskeratosis congenita 4 (DKCB4). Most mutations in the TERT gene in hTERT amino acid change, causing unstable or dysfunctional. Both mutations in the TERC gene such as mutations in the TERT gene, causing dysfunction of telomerase, deterioration in maintenance of telomeres and reducing telomere length.

The TINF2 gene, located on the long arm of chromosome 14 (14q12), encodes part of protein complex shelterin. This complex consists of a group of proteins that act together to help maintain telomeres found at the ends of chromosomes. Shelterin complex helps protect telomere DNA repair process of the cell. They have identified at least 15 TINF2 gene mutations in people with dyskeratosis congenita. Mutations in this gene result in autosomal dominant dyskeratosis congenita 3 (DKCA3), autosomal dominant dyskeratosis congenita 5 (DKCA5) and severe forms of the disease including Hoyeraal-Hreidaarsson syndrome and syndrome Revesz. Most mutations replaced amino acids in the protein TINF2, causing disruption of protein function. This causes dysfunction shelterin complex interfering with protection of telomeres and resulting in reducing telomere length.

Mutations in genes Nop10, located on the long arm of chromosome 15 (15q14-Q15) and NHP2 gene, located on the long arm of chromosome 5 (5q35.3), give rise to two variants of the disease called dyskeratosis autosomal recessive congenital 1 (DKCB1) and dyskeratosis congenita autosomal recessive 2 (DKCB2). These genes are required for ribosome biogenesis and maintenance of telomeres. But common variables include premature aging, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis and hepatic fibrosis, among others. Often, early mortality associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.

Mutations in Wrap53, located on the short arm of chromosome 17 (17p13.1) lead to an autosomal recessive dyskeratosis congenita 3 (DKCB3). Wrap53 encodes a ribonucleoprotein complex necessary for the synthesis of telomeres essential component of telomerase holoenzyme complex,. This protein is enriched in Cajal bodies, nuclear RNP processing sites that are important to the function of telomerase. This protein interacts with dyskerin, TERT and TERC, other components of the active telomerase, and small Cajal body RNAs (scaRNAs), which are involved in modifying the RNA splicing. Mutations in the Wrap53 coding leads to an altered protein that impairs normal traffic of telomerase, leading to a loss of telomerase complex components, including Wrap53, Dyskerin, and TERC of Cajal bodies.

The RTEL1 gene, located on the long arm of chromosome 20 (20q13.3), encodes a DNA helicase function with stability, protection and telomere elongation, and interacts with proteins in complex shelterin known to protect telomeres during the DNA copy. Mutations in this gene have been associated with autosomal dominant dyskeratosis congenita, 4 (DKCA4) and autosomal recessive dyskeratosis congenita 5 (DKCB5). DKCB5, it is characterized by the appearance of bone marrow failure and immunodeficiency in early childhood. Most patients with DKCB5 also have stunted growth and development and cerebellar hypoplasia, consistent with a clinical diagnosis of Hoyeraal-Hreidarsson (HHS) syndrome. Mutations in the gene RTEL1 have also been found in patients with dyskeratosis congenital phenotype comprising a characteristic of short telomeres dyskeratosis congenita and in the absence of the typical triad diagnostic DKC.

Dyskeratosis congenita may have different patterns of inheritance. When the disease is due to mutations in the DKC1 gene is inherited recessive pattern with an X - linked In males, an altered copy of the gene in each cell is sufficient for alteration is expressed. In women, a mutation would have to happen in both copies of the gene to cause the disease. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. When the disease is due to mutations in other genes, it can be inherited in an autosomal dominant or autosomal recessive. The autosomal dominant pattern means that a copy of the altered gene in each cell is sufficient for alteration is expressed. In the autosomal recessive both gene copies in each cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with different types of dyskeratosis congenita, by complete PCR amplification of the exons of TERT, TERC, DKC1, TINF2, Nop10, NHP2, Wrap53 and RTEL1 genes, respectively and subsequent sequencing. It is recommended to avoid unnecessary tests try to identify the most likely type of congenital dyskeratosis, according to patient characteristics and inheritance pattern.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).