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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Bibliographic Details
Published in:PloS one 2011-09, Vol.6 (9), p.e24383-e24383
Main Authors: Vulliamy, Tom J, Kirwan, Michael J, Beswick, Richard, Hossain, Upal, Baqai, Charlotte, Ratcliffe, Anna, Marsh, Judith, Walne, Amanda, Dokal, Inderjeet
Format: Article
Language:English
Subjects:
Adolescent
Adult
Analysis
Anemia
Aplastic anemia
Biology
Bone marrow
Cancer
Cell division
Child
Child, Preschool
Chromosomes
Dentistry
Deoxyribonucleic acid
DNA
Dyskeratosis
Gene mutation
Genetic aspects
Humans
Incidence
Infant
Leukemia
Medicine
Middle Aged
Mutation
Mutation - genetics
Patients
Ribonucleic acid
RNA
RNA-directed DNA polymerase
Severity of Illness Index
Subgroups
Telomerase
Telomerase - genetics
Telomere Homeostasis
Telomere-Binding Proteins - genetics
Telomeres
Young Adult
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0024383