162 research outputs found
Telomere biology disorders: time for moving towards the clinic?
Telomere biology disorders (TBDs) are a group of rare diseases caused by mutations that impair telomere maintenance. Mutations that cause reduced levels of TERC/hTR, the telomerase RNA component, are found in most TBD patients and include loss-of-function mutations in hTR itself, in hTR-binding proteins [NOP10, NHP2, NAF1, ZCCHC8, and dyskerin (DKC1)], and in proteins required for hTR processing (PARN). These patients show diverse clinical presentations that most commonly include bone marrow failure (BMF)/aplastic anemia (AA), pulmonary fibrosis, and liver cirrhosis. There are no curative therapies for TBD patients. An understanding of hTR biogenesis, maturation, and degradation has identified pathways and pharmacological agents targeting the poly(A) polymerase PAPD5, which adds 3'-oligoadenosine tails to hTR to promote hTR degradation, and TGS1, which modifies the 5'-cap structure of hTR to enhance degradation, as possible therapeutic approaches. Critical next steps will be clinical trials to establish the effectiveness and potential side effects of these compounds in TBD patients
Dyskeratosis Congenita links telomere attrition to age-related systemic energetics.
Underlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence associated metabolites in fibroblast conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/ mass spectrometry and liquid chromatography/ mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species (1-3). Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human ageing in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function
Targeted resequencing of 52 bone marrow failure genes in patients with aplastic anemia reveals an increased frequency of novel variants of unknown significance only in SLX4
The Loss of Telomerase Activity in Highly Differentiated CD8+CD28−CD27− T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation
The enzyme telomerase is essential for maintaining the replicative capacity of memory T cells. Although CD28 costimulatory signals can up-regulate telomerase activity, human CD8 + T cells lose CD28 expression after repeated activation. Nevertheless, telomerase is still inducible in CD8 + CD28 − T cells. To identify alternative costimulatory pathways that may be involved, we introduced chimeric receptors containing the signaling domains of CD28, CD27, CD137, CD134, and ICOS in series with the CD3 zeta (ζ) chain into primary human CD8 + T cells. Although CD3 ζ-chain signals alone were ineffective, triggering of all the other constructs induced proliferation and telomerase activity. However, not all CD8 + CD28 − T cells could up-regulate this enzyme. The further fractionation of CD8 + CD28 − T cells into CD8 + CD28 − CD27 + and CD8 + CD28 − CD27 − subsets showed that the latter had significantly shorter telomeres and extremely poor telomerase activity. The restoration of CD28 signaling in CD8 + CD28 − CD27 − T cells could not reverse the low telomerase activity that was not due to decreased expression of human telomerase reverse transcriptase, the enzyme catalytic subunit. Instead, the defect was associated with decreased phosphorylation of the kinase Akt, that phosphorylates human telomerase reverse transcriptase to induce telomerase activity. Furthermore, the defective Akt phosphorylation in these cells was specific for the Ser 473 but not the Thr 308 phosphorylation site of this molecule. Telomerase down-regulation in highly differentiated CD8 + CD28 − CD27 − T cells marks their inexorable progress toward a replicative end stage after activation. This limits the ability of memory CD8 + T cells to be maintained by continuous proliferation in vivo
Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease.
Medical Research Council, Children with Cancer and Bloodwise
Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia
The Brazilian National Council for Scientific and
Technological Development), Bloodwise, Children with Cancer and MRC (Medical
Research Council, UK)
Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations
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 credited
Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis
Financial support provided by The Medical Research Council-MR/K000292/1, Children with Cancer- 2013/144 and Blood Wise-14032 (AJW, LC, SC, AE, TV, HT and ID). KMG is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre
Cobalamin deficiency resulting in a rare haematological disorder: a case report
INTRODUCTION: We present the case of a patient with a cobalamin deficiency resulting in pancytopaenia, emphasizing the importance to define, diagnose and treat cobalamin deficiency. CASE PRESENTATION: A 52-year-old man from the Democratic Republic of Congo presented to the emergency department with shortness of breath and a sore tongue. Physical examination was unremarkable. His haemoglobin was low and the peripheral blood smear revealed pancytopaenia with a thrombotic microangiopathy. The findings were low cobalamin and folate levels, and high homocysteine and methylmalonate levels. Pernicious anaemia with chronic atrophic gastritis was confirmed by gastric biopsy and positive antiparietal cell and anti-intrinsic factor antibodies. Cobalamin with added folate was given. Six months later, the patient was asymptomatic. CONCLUSION: Cobalamin deficiency should always be ruled out in a patient with pancytopaenia. Our case report highlights a life-threatening cobalamin deficiency completely reversible after treatment
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