The telomere syndromes

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [90] Aviv, A. Genetics of leukocyte telomere length and its role in atherosclerosis. Mutat. Res. 730, 68–74 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Telomere disorders most commonly manifest as adult-onset disease and as a consequence of germline TERT or TR loss-of-function mutations13.”

What the sources say

• Not checked yetcites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [95] Hemann, M. T. et al. Telomere dysfunction triggers developmentally regulated germ cell apoptosis. Mol. Biol. Cell 12, 2023–2030 (2001). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [63] Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16. source
• Not checked yetcites [64] Keller, R. B. et al. CTC1 mutations in a patient with dyskeratosis congenita. Pediatr. Blood Cancer 59, 311–314 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“This idea is consistent with the fact that telomerase activity is upregulated in most human cancers, which probably contributes to sustaining their immortality7.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

In the paper

“Telomere elongation is cell-cycle-regulated; telomerase elongates telomeric DNA by adding telomere repeats during S phase and into M phase32,33.”

What the sources say

• Not checked yetcites [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 yetcites [33] Marcand, S., Brevet, V., Mann, C. & Gilson, E. Cell cycle restriction of telomere elongation. Curr. Biol. 10, 487–490 (2000). source

In the paper

“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.”

What the sources say

• Not checked yetcites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source

In the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source

In the paper

“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.”