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Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations

The bone marrow failure syndrome dyskeratosis congenita (DC) has been considered to be a disorder of telomere maintenance in which disease features arise due to accelerated shortening of telomeres. By screening core components of the telomerase and shelterin complexes in patients with DC and related...

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Autores principales: Vulliamy, Tom J., Kirwan, Michael J., Beswick, Richard, Hossain, Upal, Baqai, Charlotte, Ratcliffe, Anna, Marsh, Judith, Walne, Amanda, Dokal, Inderjeet
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172236/
https://www.ncbi.nlm.nih.gov/pubmed/21931702
http://dx.doi.org/10.1371/journal.pone.0024383
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author Vulliamy, Tom J.
Kirwan, Michael J.
Beswick, Richard
Hossain, Upal
Baqai, Charlotte
Ratcliffe, Anna
Marsh, Judith
Walne, Amanda
Dokal, Inderjeet
author_facet Vulliamy, Tom J.
Kirwan, Michael J.
Beswick, Richard
Hossain, Upal
Baqai, Charlotte
Ratcliffe, Anna
Marsh, Judith
Walne, Amanda
Dokal, Inderjeet
author_sort Vulliamy, Tom J.
collection PubMed
description The bone marrow failure syndrome dyskeratosis congenita (DC) has been considered to be a disorder of telomere maintenance in which disease features arise due to accelerated shortening of telomeres. By screening core components of the telomerase and shelterin complexes in patients with DC and related bone marrow failure syndromes we have identified 24 novel mutations: 11 in the RNA component of telomerase (TERC), 8 in the reverse transcriptase component (TERT), 4 in dyskerin (DKC1) and 1 in TRF1-interacting nuclear factor 2 (TINF2). This has prompted us to review these genetic subtypes in terms of telomere length, telomerase activity and clinical presentation among 194 genetically characterised index cases recruited onto the registry in London. While those with DKC1 and TINF2 mutations present at a younger age and have more disease features than those with TERC or TERT mutations, there is no difference in telomere length between these groups. There is no difference in the age of onset and numbers of disease features seen in those with TERC and TERT mutations despite the fact that the latter show higher levels of telomerase activity in vitro. The incidence of aplastic anaemia is greater in patients with TERC or TINF2 mutations compared to patients with DKC1 mutations, and cancer incidence is highest in patients with TERC mutations. These data are the first to provide robust comparisons between different genetic subtypes of telomerase and shelterin mutations (the “telomereopathies”) and clearly demonstrate that disease severity is not explained by telomere length alone.
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spelling pubmed-31722362011-09-19 Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations Vulliamy, Tom J. Kirwan, Michael J. Beswick, Richard Hossain, Upal Baqai, Charlotte Ratcliffe, Anna Marsh, Judith Walne, Amanda Dokal, Inderjeet PLoS One Research Article The bone marrow failure syndrome dyskeratosis congenita (DC) has been considered to be a disorder of telomere maintenance in which disease features arise due to accelerated shortening of telomeres. By screening core components of the telomerase and shelterin complexes in patients with DC and related bone marrow failure syndromes we have identified 24 novel mutations: 11 in the RNA component of telomerase (TERC), 8 in the reverse transcriptase component (TERT), 4 in dyskerin (DKC1) and 1 in TRF1-interacting nuclear factor 2 (TINF2). This has prompted us to review these genetic subtypes in terms of telomere length, telomerase activity and clinical presentation among 194 genetically characterised index cases recruited onto the registry in London. While those with DKC1 and TINF2 mutations present at a younger age and have more disease features than those with TERC or TERT mutations, there is no difference in telomere length between these groups. There is no difference in the age of onset and numbers of disease features seen in those with TERC and TERT mutations despite the fact that the latter show higher levels of telomerase activity in vitro. The incidence of aplastic anaemia is greater in patients with TERC or TINF2 mutations compared to patients with DKC1 mutations, and cancer incidence is highest in patients with TERC mutations. These data are the first to provide robust comparisons between different genetic subtypes of telomerase and shelterin mutations (the “telomereopathies”) and clearly demonstrate that disease severity is not explained by telomere length alone. Public Library of Science 2011-09-13 /pmc/articles/PMC3172236/ /pubmed/21931702 http://dx.doi.org/10.1371/journal.pone.0024383 Text en Vulliamy et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vulliamy, Tom J.
Kirwan, Michael J.
Beswick, Richard
Hossain, Upal
Baqai, Charlotte
Ratcliffe, Anna
Marsh, Judith
Walne, Amanda
Dokal, Inderjeet
Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
title Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
title_full Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
title_fullStr Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
title_full_unstemmed Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
title_short Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
title_sort differences in disease severity but similar telomere lengths in genetic subgroups of patients with telomerase and shelterin mutations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172236/
https://www.ncbi.nlm.nih.gov/pubmed/21931702
http://dx.doi.org/10.1371/journal.pone.0024383
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