The gastrointestinal manifestations of telomere‐mediated disease

Jonassaint, Naudia; Guo, Nini; Califano, Joseph A.; Montgomery, Elizabeth A.; Armanios, Mary

doi:10.1111/acel.12041

Cited by 91 publications

(79 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Characteristics of affected subjects from the nine RTEL1 RV families (shown in Table 2) were similar to others in the WES cohort, and previously described FIP cohorts (3). Notably, we found no evidence for a family history or clinical features of DC or HHS, including hematopoietic malignancy or aplastic anemia (25).…”

Section: Resultssupporting

confidence: 84%

Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia

Cogan

Kropski

Zhao³

et al. 2015

Am J Respir Crit Care Med

178

123

View full text Add to dashboard Cite

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds. Measurements and Main Results:We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (,10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

show abstract

Section: Resultssupporting

confidence: 84%

Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia

Cogan

Kropski

Zhao³

et al. 2015

Am J Respir Crit Care Med

178

123

View full text Add to dashboard Cite

show abstract

“…The cellular responses to telomere dysfunction are also distinct. In high-turnover epithelial tissues such as the intestinal tract, telomere dysfunction preferentially induces apoptosis (32,33,38). On the other hand, AEC2s, in both short-telomere mice (7) and in the conditional model we generated, preferentially undergo senescence.…”

Section: Senescence Is a Preferred Response To Telomere Dysfunction Inmentioning

confidence: 95%

Telomere dysfunction causes alveolar stem cell failure

Alder

Barkauskas²,

Limjunyawong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

276

273

View full text Add to dashboard Cite

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

show abstract

“…51 and Figure 1). For example, telomere syndromes in infancy manifest as severe immunodeficiency, which affects B cells, T cells, and NK cells, coincident with the extraordinary replicative demands on the adaptive immune system during this period of development (42,52,53). Bone marrow phenotypes tend to appear later in children and young adults as isolated cytopenias or aplastic anemia (43,45,51,54).…”

Section: Telomere-mediated Disease Manifests As Stem Cell Failure In mentioning

confidence: 99%

“…The telomere-mediated bone marrow failure phenotype is stem cell autonomous because allogeneic stem cell transplantation can reverse this state. The gastrointestinal epithelium, another high-turnover compartment, is also affected in a subset of patients who develop an enteropathy marked by villous blunting that resembles celiac disease (53). These intestinal phenotypes are similarly thought to be caused by stem cell failure that appears as villous atrophy in mice with short telomeres (18,58).…”

Section: Telomere-mediated Disease Manifests As Stem Cell Failure In mentioning

confidence: 99%

Telomeres and age-related disease: how telomere biology informs clinical paradigms

2013

Self Cite

View full text Add to dashboard Cite

Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies.Understanding basic biological mechanisms holds the potential to advance clinical paradigms. The emerging impact of telomerase and telomere biology in medicine provides a clear example of this promise. Research in this area was initially sparked by fundamental questions about how genomes are protected at chromosome ends, and focused on curiosity-driven questions in maize, yeast, and protozoa (1). These highly conserved molecular mechanisms have now led to unforeseen benefits for understanding idiopathic disease and have opened a new area of translational research. Here I review the trajectory of the evolving role of telomere biology in clinical paradigms and highlight how it has become central to understanding the pathophysiology of age-dependent disorders as well as for informing new approaches to their treatment.

show abstract

The gastrointestinal manifestations of telomere‐mediated disease

Cited by 91 publications

References 42 publications

Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia

Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia

Telomere dysfunction causes alveolar stem cell failure

Telomeres and age-related disease: how telomere biology informs clinical paradigms

Contact Info

Product

Resources

About