Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure

ArticleinBlood Cells Molecules and Diseases 37(2):134-6 · September 2006with7 Reads
DOI: 10.1016/j.bcmd.2006.07.001 · Source: PubMed
    • "Some mutations in Tin2 as well as genetic variants of TRF1 have been described linked to the rare human diseases dyskeratosis congenita and aplastic anaemia. These conditions [31–33] have as hallmarks epithelial abnormalities, such as skin hyperpigmentation, nail dystrophy and oral leukoplakia. "
    [Show abstract] [Hide abstract] ABSTRACT: Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-binding proteins are both important for telomere protection. Furthermore, telomere length and integrity are regulated by a number of epigenetic modifications, thus pointing to higher order control of telomere function. In this regard, we have recently discovered that telomeres are transcribed generating long, non-coding RNAs, which remain associated with the telomeric chromatin and are likely to have important roles in telomere regulation. In the past, we showed that telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of stem cells. These effects of telomerase and telomere length on stem cell behaviour anticipate the premature ageing and cancer phenotypes of telomerase mutant mice. Recently, we have demonstrated the anti-ageing activity of telomerase by forcing telomerase expression in mice with augmented cancer resistance. Shelterin is the major protein complex bound to mammalian telomeres; however, its potential relevance for cancer and ageing remained unaddressed to date. To this end, we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1 and Rap1. The study of these mice demonstrates that telomere dysfunction, even if telomeres are of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromosomal aberrations and initiation of neoplastic lesions. These new mouse models, together with the telomerase-deficient mouse model, are valuable tools for understanding human pathologies produced by telomere dysfunction.
    Full-text · Article · Jan 2011
    • "These bone density complications may be further exacerbated by the use of corticosteroids after HSCT for graft versus host disease (GVHD) prophylaxis and/or treatment. Avascular necrosis of the hips has led to hip replacement surgery in some patients [30]. Ophthalmic problems include obstruction of the lacrimal drainage system leading to constant tearing (epiphora), and abnormal eyelash growth which can cause corneal erosions or ulcers [54;61]. "
    [Show abstract] [Hide abstract] ABSTRACT: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized clinically by the triad of abnormal nails, reticular skin pigmentation, and oral leukoplakia, and is associated with high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. Patients have very short germline telomeres, and approximately half have mutations in one of six genes encoding proteins that maintain telomere function. Accurate diagnosis of DC is critical to ensure proper clinical management, because patients who have DC and bone marrow failure do not respond to immunosuppressive therapy and may have increased morbidity and mortality associated with hematopoietic stem cell transplantation.
    Full-text · Article · May 2009
  • Article · · Hematology/oncology clinics of North America
Show more