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.
Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.
Summary. To address the association between travel and deep vein thrombosis (DVT) we examined the risk factors for DVT in 568 consecutive patients with suspected DVT attending King's College Hospital in London. No significant link between DVT and long-haul travel was demonstrable in this cohort, with an odds ratio of 1AE3 (CI 0AE6-2AE8). Risk of DVT was only increased in long-haul travellers if one or more additional risk factors were present, with an odds ratio of 3AE0 (CI 1AE1-8AE2). Such individuals may benefit from prophylactic measures to minimize risk.Keywords: deep vein thrombosis, airline flights, long-haul travel, risk factors, thromboprophylaxis.The link between travel and venous thrombo-embolism (VTE) remains a contentious one (Cruickshank et al, 1988;Hirsh & O'Donnell, 2001). Two previous French casecontrol studies provided evidence for the link between travel and venous thrombosis, with odds ratios of 4AE0 (Ferrari et al, 1999) and 2AE3 (Samama, 2000), respectively, in subjects undertaking long-distance travel by air and ground transportation. A further Dutch study, however, failed to show a relationship between venous thrombosis and travel (Kraaijenhagen et al, 2000). This case-control study used subjects presenting with similar symptoms in whom venous thrombosis was excluded as controls. For air travel the odds ratio (OR) and 95% confidence interval (CI) was 1AE0 (CI 0AE3-1AE4) and for any travel was 0AE7 (CI 0AE3-1AE4). Of note, only 17 of all 788 (2AE2%) participants and 4 of 186 (2AE2%) patients with confirmed DVT had a recent history of plane travel. The debate regarding flight-related risk was reopened by a recently published randomized trial which suggested that symptomless DVT might occur in up to 10% subjects following long-haul flights (Scurr et al, 2001). To address the association between travel and thrombosis we examined the risk factors for DVT in our patient population. PATIENTS AND METHODSWe prospectively determined risk factors for VTE in a cohort of 568 consecutive outpatients with clinically suspected DVT attending the DVT Clinic at King's College Hospital in south London. Referrals originated from the hospital's emergency department as well as primary care. Camberwell has an ethnically diverse population and is not located in close proximity to an airport. A medical history was taken at presentation using a standardized proforma with questions regarding travel and known risk factors for VTE comprising hormonal therapies, surgery, malignancy, immobilization, pregnancy, obesity, previous thrombosis and significant family history. A full travel history was taken and details recorded of air or surface journeys of more than 3-h duration in the preceding 4 weeks. In view of the ongoing debate regarding the relevance of short periods of travel, we also selected those subjects who undertook longhaul flights (greater than 8 h) for detailed study. The diagnosis of DVT was confirmed using duplex ultrasonography. We calculated the OR and CI for each subgroup. RESULTSFive hundred and sixty-e...
Aplastic anemia (AA) and myelodysplasia (MDS) are forms of bone marrow failure that are often part of the same progressive underlying disorder. While most cases are simplex and idiopathic, some show a clear pattern of inheritance; therefore, elucidating the underlying genetic cause could lead to a greater understanding of this spectrum of disorders. We used a combination of exome sequencing and SNP haplotype analysis to identify causative mutations in a family with a history of autosomal-dominant AA/MDS. We identified a heterozygous mutation in SRP72, a component of the signal recognition particle (SRP) that is responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum. A subsequent screen revealed another autosomal-dominant family with an inherited heterozygous SRP72 mutation. Transfection of these sequences into mammalian cells suggested that these proteins localize incorrectly within the cell. Furthermore, coimmunoprecipitation of epitope-tagged SRP72 indicated that the essential RNA component of the SRP did not fully associate with one of the SRP72 variants. These results suggest that inherited mutations in a component of the SRP have a role in the pathophysiology of AA/MDS, identifying a third pathway for developing these disorders alongside transcription factor and telomerase mutations.
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