Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of cytokines have been shown to have stimulatory activity on multipotent haematopoietic precursors. These include kit ligand (KL), interleukins (IL) 1, 3 and 6 and granulocyte macrophage-colony stimulating factor (GM-CSF). Using reverse transcriptase/polymerase chain reaction method (RT/PCR) we have examined the expression of these cytokines, the c-kit and IL-6 receptors, in long-term bone marrow culture (LTC) adherent layer cells in human bone marrow hypoplasia syndromes. Disorders studied include Fanconi's anaemia (FA, n = 16), idiopathic aplastic anaemia (AA, n = 11), Seckel's syndrome (n = 2), dyskeratosis congenita (n = 2), Shwachman-Diamond syndrome (n = 1), thrombocytopenia with absent radii syndrome (n = 1), acquired amegakaryocytosis (n = 1), paroxysmal nocturnal haemoglobinuria (n = 1) and acquired agranulocytosis (n = 1). IL-6 and GM-CSF expression appeared reduced in most patients with FA, suggesting that impaired production of these cytokines may contribute to the bone marrow failure seen in most patients with FA. In contrast, abundant IL-6 and GM-CSF expression were seen in most patients with AA when compared with the FA group and controls; these may be mediators of a stromal response in this disorder. No obvious differences were seen between the different patients' groups and controls in expression of the other cytokines or cytokine receptors studied.
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PMID:The expression of cytokine and cytokine receptor genes in long-term bone marrow culture in congenital and acquired bone marrow hypoplasias. 751 72

Specialized nucleoprotein structures, termed telomeres, cap the ends of human chromosomes. These terminal structures, composed of repetitive arrays of guanine-rich hexameric DNA together with specific telomere-binding proteins, play essential roles in protecting the chromosome from damage and degradation. In addition, several lines of evidence implicate telomere maintenance as an important regulator of cell life span. Activation of telomerase, a dedicated reverse transcriptase that synthesizes telomeric sequences, is strongly associated with cancer, and recent observations confirm that telomeres and telomerase perform important roles in both suppressing and facilitating malignant transformation. These dual functions of telomere biology are evident in the clinical manifestations of the multisystem syndrome, dyskeratosis congenita, forms of which display defects in telomerase function. Recent advances in our understanding of telomere biology indicate that the manipulation of telomeres and telomerase will lead to clinically significant applications in the diagnosis, prevention, and treatment of neoplastic disease.
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PMID:Role of telomeres and telomerase in the pathogenesis of human cancer. 1274 59

Telomeres are composed of the tandem DNA repeats and associated proteins that cap the end of linear chromosomes. They provide stability to the chromosome and protect against DNA loss associated with cellular replication. Telomeres are maintained by the reverse transcriptase, telomerase. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation. Hematopoietic stem cells have an impressive but finite proliferative potential and demonstrate telomeric shortening during replicative aging despite expression of low levels of telomerase. Recently, the important role of telomeres in human illness has been highlighted by studies of the rare genetic disorder dyskeratosis congenita. Here we review the role of telomeres and telomerase in the function and regulation of the hematopoietic stem cell compartment and their importance in hematologic disease.
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PMID:Telomeres, telomerase, and hematopoietic stem cell biology. 1473 88

Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability.
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PMID:Telomere length variation and telomerase activity expression in patients with congenital and acquired aplastic anemia. 1503 32

Telomerase is a ribonucleoprotein complex that is required to synthesize DNA repeats at the ends of each chromosome. The RNA component of this reverse transcriptase is mutated in the bone marrow failure syndrome autosomal dominant dyskeratosis congenita. Here we show that disease anticipation is observed in families with this disease and that this is associated with progressive telomere shortening.
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PMID:Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. 1511 75

Telomerase, whose core components are a reverse transcriptase (TERT) and an integral RNA (TERC) maintains telomere ends. In somatic cells in the absence of telomerase telomeres get shorter leading to replicative cell senescence. In cancer cells abundant telomerase is present and cells do not senesce. Hence levels of telomerase may be crucial in regulating senescence and the transition to the neoplastic state. Heterozygous TERC mutations in man have been shown to underlie the rare inherited skin and bone marrow failure condition dyskeratosis congenita and a number of patients initially classified as idiopathic aplastic anemia have also been found to be mutated in one allele of the TERC gene. Families in which TERC mutations are segregating show disease anticipation, the severity of the disease increasing in successive generations due to decreasing telomere length. These data, along with biochemical analysis of mutated Terc and studies of Terc deficient mice show that in man and mouse haploinsufficiency for TERC leads to inability to correctly maintain telomeres, and highlights the importance of finely controlled telomerase levels in striking a balance between the processes of aging and cancer. Here we review several scenarios in which telomerase levels are disturbed, in human diseases or following genetic manipulation in mice.
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PMID:Heterozygous telomerase deficiency in mouse and man: when less is definitely not more. 1532 92

Human telomerase has two core components, the RNA molecule (TERC) that provides the template for telomere repeat elongation and a reverse transcriptase (TERT) that is responsible for the addition of telomere repeats at the ends of each chromosome. Mutations in TERC have been found in the autosomal-dominant form of the inherited bone marrow failure syndrome dyskeratosis congenita and in a subset of patients with aplastic anemia and myelodysplasia. These patients have short telomeres compared to age-matched controls. These observations suggest that uncharacterised cases of dyskeratosis congenita/aplastic anemia may have mutations in TERT or other molecules that associate with TERC in the telomerase complex. We have therefore screened the TERT gene for mutation by denaturing HPLC in 80 patients with inherited and acquired bone marrow failure (24 with dyskeratosis congenita, 36 with constitutional aplastic anemia, 13 with idiopathic aplastic anemia and 7 with other forms of bone marrow failure). 15 different TERT mutations have been identified. Of these, 5 are in flanking intron sequences, 6 are synonymous and 4 are non-synonymous (missense) substitutions in the coding sequence. These are the first natural mutations of TERT to be described and we highlight their possible pathogenic role in the development of bone marrow failure.
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PMID:Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. 1693 4

Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenita display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.
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PMID:Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. 1624 10

Dyskeratosis congenita is an inherited syndrome characterised by mucocutaneous features, bone marrow failure, an increased risk of malignancy and other somatic abnormalities. There is a considerable range of clinical severity and in its occult form the disease may present as idiopathic aplastic anaemia. Genes responsible for X-linked, autosomal dominant and autosomal recessive forms of the disease have been identified and been found to encode products involved in telomere maintenance. Premature shortening of telomeres could account for the pathology, affecting the tissues that turn over most rapidly. However, the protein that is mutated in the X-linked disease, dyskerin, also plays a fundamental role in ribosome biogenesis, directing the pseudouridylation of ribosomal RNA using H/ACA small nucleolar RNAs as guides. Heterozygous mutations in the RNA component of telomerase (TERC) cause the autosomal dominant form of the disease through haploinsufficiency. Disease anticipation described in these families is associated with progressive telomere shortening through the generations. Heterozygous mutations in the reverse transcriptase component of telomerase (TERT) have a more variable role, often displaying incomplete penetrance and diverse clinical presentation. The autosomal recessive form of the disease is genetically heterogeneous, although one sub-type has been described in which NOP10 is mutated. This small protein is also associated with the maturation of ribosomal RNA and the telomerase complex.
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PMID:Dyskeratosis congenita: the diverse clinical presentation of mutations in the telomerase complex. 1782 70

Heterozygous mutations in the telomerase components TERT, the reverse transcriptase, and TERC, the RNA template, cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres, is a feature of this condition. Here we describe 2 families in which 2 TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution, while his father's second allele encodes an H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show codominant expression of the mutated alleles with no evidence of a dominant negative effect or of intragenic complementation. Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype.
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PMID:Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene. 1804 1


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