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Cited by 982Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsNuclear Structure and Function

The telomere syndromes

Open access
Armanios, Mary, Blackburn, Elizabeth H.·2012·Nature Reviews Genetics
DOI 10.1038/nrg3246PMC PMC3548426
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Abstract

There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.

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Crossref · 10.1038/nrg3246

Cites

128 of 128 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 123 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Telomere dysfunction plays a causal role in multiple degenerative disorders.

    “There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders.”
    • Also stated in: § Abstract · boosted
      “This Review highlights how recent discoveries in human genetics have synergized with the field of telomere biology to unequivocally establish a causal role for telomere dysfunction in several specific, common and recognizable disease contexts.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Idiopathic pulmonary fibrosis is the most frequent disease manifestation caused by telomere defects.

    “Among these, the lung disease idiopathic pulmonary fibrosis (IPF) — best known until recently by its ‘idiopathic’ adjective — is the most common manifestation of telomere-mediated disease12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Armanios, M. Telomerase and idiopathic pulmonary fibrosis. Mutat. Res. 730, 52–58 (2012). source

      Not checked in the free run.

  • Interpretationreasoning

    Telomere length is an inherited trait.

    “Because, as we discuss, telomere length is heritable, the unique inheritance patterns that distinguish these syndromes from other Mendelian disorders are also discussed.”
    • Also stated in: § Heritability of telomere length in humans · plain
      “These observations collectively support that telomere length is a genetically determined trait and that short telomeres are probably sufficient to cause disease phenotypes within similar thresholds to those seen in monogenic disorders.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Short telomeres are likely sufficient on their own to produce disease phenotypes at thresholds comparable to those in monogenic disorders.

    “These observations collectively support that telomere length is a genetically determined trait and that short telomeres are probably sufficient to cause disease phenotypes within similar thresholds to those seen in monogenic disorders.”
    Quote in the paperSubstantial claim
  • Premisenone given

    TERT and TR mutations are the most frequently identified genetic defects in monogenic telomere syndromes.

    “Mutations in TERT and TR are the most commonly identifiable defects in monogenic telomere syndromes.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 23

  • May combine two claims.

    Premisecitation

    Because losing function of a single TERT or TR allele is enough to impair telomere maintenance, these mutations follow autosomal-dominant inheritance.

    “They manifest in an autosomal-dominant inheritance pattern because complete or partial loss-of-function of one allele is sufficient to perturb telomere maintenance38,39,41.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [38] Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001). source

      Not checked in the free run.

    • cites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source

      Not checked in the free run.

    • cites [41] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). This study identified TERT mutations in patients with aplastic anaemia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human population and twin studies indicate that parental telomere length, especially paternal, affects offspring telomere length, with heritability estimates between 0.36 and 0.84.

    “In addition to studies in families, a number of population-based twin and non-twin studies have shown that parental telomere length (especially the paternal) influences offspring telomere length with heritability estimates ranging from 0.36–0.84 (reviewed in Ref. 90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Aviv, A. Genetics of leukocyte telomere length and its role in atherosclerosis. Mutat. Res. 730, 68–74 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Mouse studies show that telomere length is inherited as a distinct genotype and can be uncoupled from the telomerase and telomere gene loci.

    “When quantified, telomere length is short in wild-type offspring of parent M. castaneus mice that have short telomeres, indicating that telomere length is inherited36,82”
    • Also stated in: § Evidence from mouse studies · plain
      “Therefore, telomere length is inherited as a unique genotype, and its inheritance can be uncoupled from the telomerase and telomere gene loci.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005). In reference 36, using CAST/EiJ mice that have telomere length similar to humans, this paper established that telomerase haploinsufficiency is sufficient to cause dyskeratosis-congenita-like phenotypes. It also showed that telomere length is inherited and can cause degenerative phenotypes even when telomerase is wild-type. source

      Not checked in the free run.

    • cites [82] Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In autosomal-dominant telomere syndrome families, pulmonary fibrosis typically appears in earlier generations, while bone marrow failure becomes the first complication in later generations.

    “In earlier generations, pulmonary fibrosis is usually the primary manifestation, whereas in later generations, bone marrow failure in younger individuals is seen as a first complication71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most telomere disorders appear in adulthood and result from inherited loss-of-function mutations in TERT or TR.

    “Telomere disorders most commonly manifest as adult-onset disease and as a consequence of germline TERT or TR loss-of-function mutations13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Signalling from short telomeres activates checkpoints that cause either senescence or apoptosis, and sometimes both at once.

    “The consequent signalling cascades activate checkpoints that induce either cellular senescence or apoptosis, and in at least some contexts both processes occur simultaneously82,85,91,95.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [82] Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009). source

      Not checked in the free run.

    • cites [85] Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998). References 84 and 85 are two landmark papers that established that telomerase itself is not essential and that short telomeres cause apoptosis and cell loss in high-turnover tissues. source

      Not checked in the free run.

    • cites [91] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source

      Not checked in the free run.

    • cites [95] Hemann, M. T. et al. Telomere dysfunction triggers developmentally regulated germ cell apoptosis. Mol. Biol. Cell 12, 2023–2030 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only about one tenth of dyskeratosis congenita cases die from cancer; the rest die from degenerative phenotypes.

    “However, the cancer-related mortality is limited to approximately 10% of dyskeratosis congenita cases, with the remaining mortality attributable to the degenerative disease phenotypes described above.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TERT or TR mutations are found in 8-15% of familial IPF and 1-3% of sporadic IPF cases.

    “The frequency of these mutations is highest in individuals with the progressive disorder IPF, which accounts for 8–15% of familial and 1–3% of sporadic cases54,56,68,69.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [54] Alder, J. K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl Acad. Sci. USA 105, 13051–13056 (2008). source

      Not checked in the free run.

    • cites [56] Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007). References 54–56 showed that lymphocyte telomere length using flow cytometry and fluorescence in situ hybridization could be a useful diagnostic marker in identifying individuals with telomere-related disease. source

      Not checked in the free run.

    • cites [68] Tsakiri, K. D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl Acad. Sci. USA 104, 7552–7557 (2007). References 56 and 68 identified mutations in the essential telomerase genes in familial pulmonary fibrosis. source

      Not checked in the free run.

    • cites [69] Cronkhite, J.T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    How short telomeres become determines both how severe the disease is and which disease type appears.

    “Hence, the degree of telomere shortness is a determinant of both disease severity and type.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Telomere-induced senescence acts mainly through p53-dependent pathways, though the RB pathway may also be involved in some contexts.

    “The downstream effector pathways of telomere-induced senescence are largely p53-dependent96, but there may be involvement of the retinoblastoma protein (RB) pathway in some settings97.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [96] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999). source

      Not checked in the free run.

    • cites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eight genes have been found mutated in dyskeratosis congenita, and every one encodes a telomerase or telomere protein component.

    “Eight mutant genes have been identified in dyskeratosis congenita9,38,39,60–64, and all of them encode telomerase or telomere protein components (summarized in Table 1).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [9] Heiss, N. S. et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genet. 19, 32–38 (1998). This study identified mutations in the X-linked DKC1 gene as a first cause of dyskeratosis congenita. source

      Not checked in the free run.

    • cites [38] Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001). source

      Not checked in the free run.

    • cites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source

      Not checked in the free run.

    • cites [60] Vulliamy, T. et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Natl Acad. Sci. USA 105, 8073–8078 (2008). source

      Not checked in the free run.

    • cites [61] Walne, A. J. et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Mol. Genet. 16, 1619–1629 (2007). source

      Not checked in the free run.

    • cites [62] Savage, S. A. et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82, 501–509 (2008). This paper was the first to show that mutations in a shelterin component are a cause of dyskeratosis congenita. source

      Not checked in the free run.

    • cites [63] Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16. source

      Not checked in the free run.

    • cites [64] Keller, R. B. et al. CTC1 mutations in a patient with dyskeratosis congenita. Pediatr. Blood Cancer 59, 311–314 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mean leukocyte telomere length is a surrogate for the mean in a mixed cell population, and telomere length is mosaic across cell types.

    “When examining telomere measurements within a mixed cell population, it is important to note that this is a surrogate marker of the mean in a heterogeneous cell population and that telomere length is mosaic, reflecting the telomere length regulation and replicative history of each cell type51,52.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] Lin, J. et al. Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance. J. Immunol. Methods 352, 71–80 (2010). source

      Not checked in the free run.

    • cites [52] Rufer, N. et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190, 157–167 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because telomerase synthesis on human telomeres is limited, telomere shortening is the default state and generally accompanies cell proliferation.

    “The limitation on the telomerase synthesis reaction on human telomeres favours telomere shortening as a general default state and means that telomere shortening generally accompanies cell proliferation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Most human cancers have increased telomerase activity, which probably helps them maintain immortality.

    “This idea is consistent with the fact that telomerase activity is upregulated in most human cancers, which probably contributes to sustaining their immortality7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994). In this study, telomerase activity was found to be enriched in cancer and germ cells, suggesting that telomerase has a role in extending replicative potential. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Because the shared short telomere defect is acquired with age, telomere syndromes are highly relevant to understanding age-related disease.

    “The telomere syndromes are highly relevant for understanding age-related disease because the short telomere defect that they share is acquired with age.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The short telomere defect shared by telomere syndromes is acquired with age.

  • May combine two claims.

    Interpretationreasoning

    The common telomere defect underlying aplastic anaemia and IPF unites previously separate clinical entities into a recognizable syndrome complex that mainly appears in adults.

    “The shared underlying telomere defect in aplastic anaemia and IPF brings together clinical entities that were previously considered to be disparate and defines a recognizable syndrome complex that predominantly manifests in adults, in contrast to dyskeratosis congenita.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Telomerase adds telomere repeats during S phase and into M phase, so elongation is cell-cycle-regulated.

    “Telomere elongation is cell-cycle-regulated; telomerase elongates telomeric DNA by adding telomere repeats during S phase and into M phase32,33.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Diede, S. J. & Gottschling, D. E. Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases α and δ. Cell 99, 723–733 (1999). source

      Not checked in the free run.

    • cites [33] Marcand, S., Brevet, V., Mann, C. & Gilson, E. Cell cycle restriction of telomere elongation. Curr. Biol. 10, 487–490 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    When IPF, bone marrow failure, and liver cirrhosis occur together, this combination is specific for and strongly predicts an inherited telomere maintenance defect.

    “Indeed, the co-occurrence of IPF and bone marrow failure, along with liver cirrhosis, is specific to and highly predictive of a germline telomere maintenance defect13,39,71.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source

      Not checked in the free run.

    • cites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source

      Not checked in the free run.

    • cites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Senescence caused by telomere dysfunction is not merely loss of replicative capacity; it can impair cell function while cells still look normal.

    “Therefore, it seems that telomere-induced senescence represents more than a loss of replicative potential and can limit cellular function even when cells appear morphologically intact97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Telomere syndromes are a model example of premature ageing because their shared short-telomere defect accumulates with age in people.

    “Telomere syndromes represent an archetype of premature-ageing syndromes because the short telomere defect they share is progressively acquired with age in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In addition to its classic effects in high-turnover tissues, telomere dysfunction can by itself produce, and often does produce, degenerative changes in slow-turnover tissues.

    “Beyond its canonical phenotypes in high-turnover tissues, telomere dysfunction is sufficient to cause — and indeed commonly causes — degenerative phenotypes in slow-turnover tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although they look normal, mouse β-cells carrying dysfunctional telomeres display senescence features: DNA damage response activation, reduced proliferation, increased p16INK4A, and changed gene expression.

    “Although they appear morphologically normal, mouse β-cells with dysfunctional telomeres show the hallmarks of senescence. They have an activated DNA damage response, impaired proliferation, p16INK4A upregulation and altered gene expression97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because telomere-driven senescence alters gene expression and thereby function without disrupting tissue structure, this reveals a new way senescence can cause disease.

    “The fact that the gene expression changes that occur during telomere-induced senescence cause functional changes in the absence of structural tissue disruption highlights a novel mechanism by which senescence and its associated gene expression changes cause disease.”
    Quote in the paperSubstantial claim
23 of 23

  • The paper relies on this without support.

    The short telomere defect shared by telomere syndromes is acquired with age.

    “The telomere syndromes are highly relevant for understanding age-related disease because the short telomere defect that they share is acquired with age.”

  • The paper relies on this without support.

    The short telomere defect in affected individuals is present in germ cells and thus simultaneously affects multiple organs even when one disease presentation predominates.

    “Their grouping together as a syndrome spectrum is crucial for clinical decisions because the short telomere defect in affected individuals is present in germ cells and thus simultaneously affects multiple organs even when one disease presentation predominates.”

  • The paper relies on this without support.

    Allogeneic stem cell transplantation can reverse aplastic anaemia in humans.

    “In humans, the aplastic anaemia phenotype can be reversed with allogeneic stem cell transplant, indicating that this telomere-related stem cell failure state is primarily cell-autonomous.”

  • The paper relies on this without support.

    Smoking hastens disease onset in people who carry telomerase mutations.

    “Instead, a second insult is required, and when mice with short telomeres are experimentally exposed to cigarette smoke, which is known to accelerate disease onset in human telomerase mutation carriers, they develop lung disease99.”

  • The paper relies on this without support.

    β-cells in adult mouse pancreatic islets turn over slowly, roughly 4% each week.

    “This mechanism has been elucidated in adult mouse β-cells of the pancreatic islets, which have a fairly slow turnover (4% per week).”

  • The paper relies on this without support.

    Blood formation depends on a small set of stem cells that can self-renew and differentiate.

    “Haematopoiesis relies on the self-renewal and differentiation capacity of a well-characterized oligoclonal stem cell compartment.”
6 of 6

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Authors
Armanios, M., & Blackburn, E. H.
Affiliations
  • Johns Hopkins University (US)
  • University of California, San Francisco (US)
Corresponding author
Armanios, Mary
ORCID
Venue
Nature Reviews Genetics
Publisher
Springer Science and Business Media LLC
Published
2012-09-11
Volume
13
Issue
10
Pages
693-704
ISSN
  • 1471-0056 (ISSN-L)
  • 1471-0064
DOI
10.1038/nrg3246
PMC
PMC3548426
OpenAlex
W1981775109
Cited by
982
References
128
Citations by year
2026: 41 · 2025: 46 · 2024: 50 · 2023: 63 · 2022: 68 · 2021: 92 · 2020: 74 · 2019: 79 · 2018: 81 · 2017: 84 · 2016: 82 · 2015: 80 · 2014: 71 · 2013: 59 · 2012: 8
FWCI
7.50
Type
journal article
Language
en
Update notices
erratum (2013-02-12)
Open access
Licence
Locations
  • Nature Reviews Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R21HL104345)
  • National Cancer Institute (R01CA160433)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
telomere dysfunction, telomere maintenance, short telomeres, cellular aging, idiopathic pulmonary fibrosis, bone marrow failure, degenerative diseases, mode of inheritance, age-related diseases, telomere biology
MeSH terms
Animals, Humans, Models, Biological, Syndrome, Telomere, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Genetic Diseases, Inborn, Genetic Association Studies

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