Abstract
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.
Highlights
Telomeres are nucleoprotein structures that protect chromosome ends, distinguishing them from double strand breaks that might occur elsewhere in the genome and need repair [1]
Through mutation screening in patients with dyskeratosis congenita (DC) and related bone marrow failure syndromes, we have identified 23 novel mutations in core components of telomerase: 11 in TERC, 8 in the reverse transcriptase component (TERT) and 4 in DKC1 (Table 1, Figures S1 and S2)
One mutation in the shelterin component TRF1-interacting nuclear factor 2 (TINF2) has been identified which is in addition to the 8 TINF2 mutations that we have recently reported elsewhere [39]
Summary
Telomeres are nucleoprotein structures that protect chromosome ends, distinguishing them from double strand breaks that might occur elsewhere in the genome and need repair [1]. Telomeric DNA consists of a TTAGGG repeat sequence that is bound by a protein complex known as shelterin [2]. Because of the end-replication problem [3] telomeres shorten with each cell division and when they become critically short, a p53-dependent checkpoint is activated that leads to apoptosis or cell senescence [4,5,6]. Telomere shortening has been linked to the processes of both aging [8] and cancer [9]. In the germ line and in some stem cells, telomeric DNA can be replenished by telomerase, a ribonucloeprotein complex that involves an RNA template and a reverse transcriptase [10]
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