Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family

Abstract Dyskeratosis Congenita (DC) is a bone marrow (BM) failure syndrome characterized by progressive telomere shortening. The discovery of mutations in genes encoding components of the telomerase complex in DC has implicated defective telomere maintenance in the disease pathogenesis. However, it is not known if defective telomeres in DC result in a qualitative impairment of hematopoiesis and/or a decrease in the maintenance of very primitive hematopoietic cells. To address this question, we characterized CD34+ cells present in BM aspirates and granulocyte colony stimulating factor (G-CSF) -mobilized peripheral blood (mPB) cells harvested from 5 DC patients prior to the onset of severe BM failure. These 5 patients were from 3 successive generations of a single family and all had an autosomal dominant mutation in the telomerase gene (TERC). The BM was found to be hypocellular in all patients, with a consistently reduced percentage of CD34+ cells - lowest in the two 3rd generation subjects (0.05% and 0.16% vs 0.5%–1% in normal controls). The target for G-CSF-mobilized cell harvests (2x106 CD34+ cells/kg) was met for 2 of the 5 DC patients, with only 5x105 CD34+ cells/kg obtained from the 2 DC patients with a longstanding history of thrombocytopenia. However, within the CD34+ population, the proportions of cells co-expressing various lineage markers were normal and the frequencies of granulopoietic, erythroid and multi-lineage colony-forming cells (CFCs) were similar to those of normal donors, suggesting that the commitment and differentiation programs in these DC patients were not grossly perturbed. However, the fact that their BMs were hypocellular with a further reduced content of CD34+ cells indicates that total CFC numbers were markedly decreased. The total number of more primitive cells detectable as long term culture-initiating cells (LTC-ICs) were decreased a further order of magnitude as indicated by a 10-fold reduction in their frequency within the CD34+ compartment by comparison to normal mPB CD34+ cells. Telomere length measurements were performed on cells from day 4 cultures of CD34+ mPB DC cells using quantitative FISH (Q-FISH) and single telomere end length analysis (STELA). Telomere length in a 2nd generation patient was reduced (7.2 Kb) compared to an age-matched control (12.4 Kb) and this difference was accentuated in two 3rd generation patients (4.6 and 3.4 Kb) in line with progressive telomere loss with successive generations. Telomeres with <1.5 kb repeats were readily observed by STELA and were increased in DC subjects (up to 9.5%). These findings provide the first description of telomere length and functional analyses of primitive hematopoietic cells from DC patients. The data support the concept that BM failure in DC subjects results from a loss of very primitive hematopoietic cells triggered by defective telomeres rather than a qualitative impairment in the ability of hematopoietic cells to differentiate. Assays of primitive cells and telomere length may thus be useful parameters to predict both the time of onset and the degree of BM failure in DC patients.

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Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase

Blood ◽

10.1182/blood-2010-11-322149 ◽

2011 ◽

Vol 117 (21) ◽

pp. 5607-5611 ◽

Cited By ~ 105

Author(s):

Erin M. Parry ◽

Jonathan K. Alder ◽

Xiaodong Qi ◽

Julian J.-L. Chen ◽

Mary Armanios

Keyword(s):

Bone Marrow ◽

Pulmonary Fibrosis ◽

Autosomal Dominant ◽

Age Of Onset ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Bone Marrow Failure Syndrome ◽

Preparative Regimen ◽

The Mean ◽

Successive Generations

Abstract Mutations in the essential telomerase components hTERT and hTR cause dyskeratosis congenita, a bone marrow failure syndrome characterized by mucocutaneous features. Some (∼ 3%) sporadic aplastic anemia (AA) and idiopathic pulmonary fibrosis cases also carry mutations in hTERT and hTR. Even though it can affect clinical outcome, because the mutation frequency is rare, genetic testing is not standard. We examined whether the cooccurrence of bone marrow failure and pulmonary fibrosis in the same individual or family enriches for the presence of a telomerase mutation. Ten consecutive individuals with a total of 36 family members who fulfilled these criteria carried a germline mutant telomerase gene (100%). The mean age of onset for individuals with AA was significantly younger than that for those with pulmonary fibrosis (14 vs 51; P < .0001). Families displayed autosomal dominant inheritance and there was an evolving pattern of genetic anticipation, with the older generation primarily affected by pulmonary fibrosis and successive generations by bone marrow failure. The cooccurrence of AA and pulmonary fibrosis in a single patient or family is highly predictive for the presence of a germline telomerase defect. This diagnosis affects the choice of bone marrow transplantation preparative regimen and can prevent morbidity.

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Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline

Life Science Alliance ◽

10.26508/lsa.202101208 ◽

2021 ◽

Vol 5 (1) ◽

pp. e202101208

Author(s):

Jacqueline V Graniel ◽

Kamlesh Bisht ◽

Ann Friedman ◽

James White ◽

Eric Perkey ◽

...

Keyword(s):

Bone Marrow ◽

Steady State ◽

Telomere Length ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Seminiferous Tubules ◽

Germline Stem Cells ◽

Morphological Defects ◽

Evolutionary Fitness ◽

Telomere Erosion

Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mutation in TPP1 (K170∆) that specifically compromises telomerase recruitment to telomeres is a valuable tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mouse knocked in for the equivalent of the TPP1 K170∆ mutation (TPP1 K82∆) and investigated both its hematopoietic and germline compartments in unprecedented detail. TPP1 K82∆ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82∆ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of dysfunctional seminiferous tubules, and a decrease in germ cells. Intriguingly, both TPP1 K82∆ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to infertility at steady-state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice.

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Through the Lens of Gurdjieff

Fieldwork in Religion ◽

10.1558/firn.31487 ◽

2016 ◽

Vol 11 (1) ◽

pp. 36-52

Author(s):

Michael Pittman

Keyword(s):

Participant Observation ◽

Field Research ◽

Spiritual Transformation ◽

Spiritual Practice ◽

Asia Minor ◽

Eastern Asia ◽

The Caucasus ◽

Successive Generations ◽

Spiritual Conversation

G. I. Gurdjieff (c.1866–1949) was born in Gyumri, Armenia and raised in the Caucasus and eastern Asia Minor. He also traveled extensively throughout Turkey to places of pilgrimage and in search of Sufi teachers. Through the lens of Gurdjieff’s notion of legominism, or the means by which spiritual teachings are transmitted from successive generations, this article explores the continuing significance of spiritual practice and tradition and the ways that these forms remain relevant in shaping contemporary trends in spirituality. Beginning with Gurdjieff’s use of legominism, the article provides reflection on some early findings done in field research in Turkey— through site visits, interviews and participant-observation—conducted in the summers of 2014 and 2015. The aim of the project is both to meet individuals and groups, particularly connected to Sufism, that may have some contact with the influences that Gurdjieff would have been familiar with, and to visit some of the sites that were part of Gurdjieff’s early background and which served to inform his work. Considerations of contemporary practices include the view of spiritual transmission, and practices of pilgrimage, prayer and sohbet, or spiritual conversation, in an ongoing discourse about spiritual transformation.

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Estimation of Genotoxic Effects from GSM Base Stations on Four Successive Generations (F1 F4) of Albino Mice, Mus Musculus Using RAPD Bands and Micronucleus Assay

Journal of Environment and Human ◽

10.15764/eh.2014.02001 ◽

2014 ◽

Vol 2014 (2) ◽

pp. 1-8

Author(s):

Aneyo Ayisat ◽

◽

Otitoloju Akeem ◽

Fowora Muinah ◽

◽

...

Keyword(s):

Mus Musculus ◽

Micronucleus Assay ◽

Base Stations ◽

Genotoxic Effects ◽

Albino Mice ◽

Successive Generations

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Editorial

Journal of Innovation Management ◽

10.24840/2183-0606_001.002_0001 ◽

2013 ◽

Vol 1 (2) ◽

pp. 1-3

Author(s):

João José Pinto Ferreira ◽

Anne-Laure Mention ◽

Marko Torkkeli

Keyword(s):

Economic Development ◽

Education Research ◽

Research And Development ◽

Research Integrity ◽

Academic Community ◽

Human Knowledge ◽

Academic Institutions ◽

Current State ◽

State Of Research ◽

Successive Generations

The expansion of human knowledge in all areas is largely the outcome of the activity of academic institutions and the result of their mission to contribute to the cultural, intellectual and economic development of the society, involving education, research and university extension activities. For many years, the academic community has been organizing itself in all different ways to respond to current and future needs, ensuring research integrity and recognition, and building on successive generations of peers to validate and support the launching and development of novel research streams. We owe the current state of research and development of our society to generations of scholars and scientists that have brought all of us here.(...)

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