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Annual Review of Genomics and Human Genetics

Volume 23, 2022

The Role of Telomeres in Human Disease

Abstract

Telomere biology was first studied in maize, ciliates, yeast, and mice, and in recent decades, it has informed understanding of common disease mechanisms with broad implications for patient care. Short telomere syndromes are the most prevalent premature aging disorders, with prominent phenotypes affecting the lung and hematopoietic system. Less understood are a newly recognized group of cancer-prone syndromes that are associated with mutations that lengthen telomeres. A large body of new data from Mendelian genetics and epidemiology now provides an opportunity to reconsider paradigms related to the role of telomeres in human aging and cancer, and in some cases, the findings diverge from what was interpreted from model systems. For example, short telomeres have been considered potent drivers of genome instability, but age-associated solid tumors are rare in individuals with short telomere syndromes, and T cell immunodeficiency explains their spectrum. More commonly, short telomeres promote clonal hematopoiesis, including somatic reversion, providing a new leukemogenesis paradigm that is independent of genome instability. Long telomeres, on the other hand, which extend the cellular life span in vitro, are now appreciated to be the most common shared germline risk factor for cancer in population studies. Through this contemporary lens, I revisit here the role of telomeres in human aging, focusing on how short and long telomeres drive cancer evolution but through distinct mechanisms.

Keyword(s): aging, cancer, clonal hematopoiesis, genome instability, pulmonary fibrosis, telomerase
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2022-08-31
2024-05-17
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Literature Cited

  1. 1.
    Alder JK, Armanios M. 2022. Telomere-mediated lung disease. Physiol. Rev. In press. https://doi.org/10.1152/physrev.00046.2021
    [Crossref] [Google Scholar]
  2. 2.
    Alder JK, Barkauskas CE, Limjunyawong N, Stanley SE, Kembou F et al. 2015. Telomere dysfunction causes alveolar stem cell failure. PNAS 112:5099–104
     [Google Scholar]
  3. 3.
    Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC et al. 2008. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. PNAS 105:13051–56
     [Google Scholar]
  4. 4.
    Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE et al. 2011. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLOS Genet 7:e1001352
     [Google Scholar]
  5. 5.
    Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ et al. 2011. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 184:904–12
     [Google Scholar]
  6. 6.
    Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE et al. 2018. Diagnostic utility of telomere length testing in a hospital-based setting. PNAS 115:E2358–65 Correction 2018. PNAS 115:E4312
     [Google Scholar]
  7. 7.
    Alder JK, Parry EM, Yegnasubramanian S, Wagner CL, Lieblich LM et al. 2013. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum. Mutat. 34:1481–85
     [Google Scholar]
  8. 8.
    Alder JK, Stanley SE, Wagner CL, Hamilton M, Hanumanthu VS, Armanios M. 2015. Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest 147:1361–68
     [Google Scholar]
  9. 9.
    Alder JK, Sutton RM, Iasella CJ, Nouraie M, Koshy R et al. 2022. Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease. J. Heart Lung Transplant. 41:654–63
     [Google Scholar]
  10. 10.
    Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV et al. 1992. Telomere length predicts replicative capacity of human fibroblasts. PNAS 89:10114–18
     [Google Scholar]
  11. 11.
    Alter BP, Giri N, Savage SA, Rosenberg PS. 2009. Cancer in dyskeratosis congenita. Blood 113:6549–57
     [Google Scholar]
  12. 12.
    Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM et al. 2012. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat. Genet. 44:338–42
     [Google Scholar]
  13. 13.
    Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M et al. 2015. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J. Natl. Cancer Inst. 107:dju408
     [Google Scholar]
  14. 14.
    Armanios M. 2009. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10:45–61
     [Google Scholar]
  15. 15.
    Armanios M. 2012. An emerging role for the conserved telomere component 1 (CTC1) in human genetic disease. Pediatr. Blood Cancer 59:209–10
     [Google Scholar]
  16. 16.
    Armanios M. 2013. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J. Clin. Investig. 123:996–1002
     [Google Scholar]
  17. 17.
    Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW. 2009. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85:823–32
     [Google Scholar]
  18. 18.
    Armanios M, Blackburn EH. 2012. The telomere syndromes. Nat. Rev. Genet. 13:693–704
     [Google Scholar]
  19. 19.
    Armanios M, Chen JJ, Cogan JD, Alder JK, Ingersoll RG et al. 2007. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356:1317–26
     [Google Scholar]
  20. 20.
    Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A et al. 2005. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. PNAS 102:15960–64
     [Google Scholar]
  21. 21.
    Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ et al. 2000. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406:641–45
     [Google Scholar]
  22. 22.
    Artandi SE, DePinho RA. 2010. Telomeres and telomerase in cancer. Carcinogenesis 31:9–18
     [Google Scholar]
  23. 23.
    Aubert G, Baerlocher GM, Vulto I, Poon SS, Lansdorp PM. 2012. Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLOS Genet. 8:e1002696
     [Google Scholar]
  24. 24.
    Aviv A. 2012. Genetics of leukocyte telomere length and its role in atherosclerosis. Mutat. Res. 730:68–74
     [Google Scholar]
  25. 25.
    Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J et al. 2013. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in dyskeratosis congenita. Hum. Genet. 132:473–80
     [Google Scholar]
  26. 26.
    Bick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL et al. 2020. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 568:763–68
     [Google Scholar]
  27. 27.
    Blackburn EH, Greider CW, Szostak JW. 2006. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med. 12:1133–38
     [Google Scholar]
  28. 28.
    Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM et al. 1997. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:25–34
     [Google Scholar]
  29. 29.
    Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S et al. 2018. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 131:717–32
     [Google Scholar]
  30. 30.
    Calado RT, Regal JA, Kleiner DE, Schrump DS, Peterson NR et al. 2009. A spectrum of severe familial liver disorders associate with telomerase mutations. PLOS ONE 4:e7926
     [Google Scholar]
  31. 31.
    Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J et al. 2013. Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet. 45:422–27
     [Google Scholar]
  32. 32.
    Codd V, Wang Q, Allara E, Musicha C, Kaptoge S et al. 2021. Polygenic basis and biomedical consequences of telomere length variation. Nat. Genet. 53:1425–33
     [Google Scholar]
  33. 33.
    Cogan JD, Kropski JA, Zhao M, Mitchell DB, Rives L et al. 2015. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am. J. Respir. Crit. Care Med. 191:646–55
     [Google Scholar]
  34. 34.
    Crow YJ, McMenamin J, Haenggeli CA, Hadley DM, Tirupathi S et al. 2004. Coats’ plus: a progressive familial syndrome of bilateral Coats’ disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument. Neuropediatrics 35:10–19
     [Google Scholar]
  35. 35.
    de Lange T. 2005. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19:2100–10
     [Google Scholar]
  36. 36.
    Dokal I. 2000. Dyskeratosis congenita in all its forms. Br. J. Haematol. 110:768–79
     [Google Scholar]
  37. 37.
    Feldser DM, Greider CW. 2007. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11:461–69
     [Google Scholar]
  38. 38.
    Feldser DM, Hackett JA, Greider CW. 2003. Telomere dysfunction and the initiation of genome instability. Nat. Rev. Cancer 3:623–27
     [Google Scholar]
  39. 39.
    Gable DL, Gaysinskaya V, Atik CC, Talbot CC Jr., Kang B et al. 2019. ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev. 33:1381–96
     [Google Scholar]
  40. 40.
    Gaysinskaya V, Stanley SE, Adam S, Armanios M 2020. Synonymous mutation in DKC1 causes telomerase RNA insufficiency manifesting as familial pulmonary fibrosis. Chest 158:2449–57
     [Google Scholar]
  41. 41.
    Glousker G, Touzot F, Revy P, Tzfati Y, Savage SA. 2015. Unraveling the pathogenesis of Hoyeraal–Hreidarsson syndrome, a complex telomere biology disorder. Br. J. Haematol. 170:457–71
     [Google Scholar]
  42. 42.
    Gorgy AI, Jonassaint NL, Stanley SE, Koteish A, DeZern AE et al. 2015. Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest 148:1019–26
     [Google Scholar]
  43. 43.
    Greider CW, Blackburn EH. 1985. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43:405–13
     [Google Scholar]
  44. 44.
    Greider CW, Blackburn EH. 1989. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–37
     [Google Scholar]
  45. 45.
    Guo Y, Kartawinata M, Li J, Pickett HA, Teo J et al. 2014. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 124:2767–74
     [Google Scholar]
  46. 46.
    Hao LY, Armanios M, Strong MA, Karim B, Feldser DM et al. 2005. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123:1121–31
     [Google Scholar]
  47. 47.
    Harley CB, Futcher AB, Greider CW. 1990. Telomeres shorten during ageing of human fibroblasts. Nature 345:458–60
     [Google Scholar]
  48. 48.
    Haycock PC, Burgess S, Nounu A, Zheng J, Okoli GN et al. 2017. Association between telomere length and risk of cancer and non-neoplastic diseases: a Mendelian randomization study. JAMA Oncol. 3:636–51
     [Google Scholar]
  49. 49.
    Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S et al. 1998. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat. Genet. 19:32–38
     [Google Scholar]
  50. 50.
    Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A et al. 2013. TERT promoter mutations in familial and sporadic melanoma. Science 339:959–61
     [Google Scholar]
  51. 51.
    Hoyeraal HM, Lamvik J, Moe PJ. 1970. Congenital hypoplastic thrombocytopenia and cerebral malformations in two brothers. Acta Paediatr. Scand. 59:185–91
     [Google Scholar]
  52. 52.
    Hreidarsson S, Kristjansson K, Johannesson G, Johannsson JH. 1988. A syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure. Acta Paediatr. Scand. 77:773–75
     [Google Scholar]
  53. 53.
    Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. 2013. Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–59
     [Google Scholar]
  54. 54.
    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV et al. 2014. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371:2488–98
     [Google Scholar]
  55. 55.
    Jeck WR, Siebold AP, Sharpless NE. 2012. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell 11:727–31
     [Google Scholar]
  56. 56.
    Jonassaint NL, Guo N, Califano JA, Montgomery EA, Armanios M. 2013. The gastrointestinal manifestations of telomere-mediated disease. Aging Cell 12:319–23
     [Google Scholar]
  57. 57.
    Keel SB, Geddis A. 2021. The clinical and laboratory evaluation of patients with suspected hypocellular marrow failure. Hematol. ASH Educ. Program 2021:134–42
     [Google Scholar]
  58. 58.
    Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S et al. 2016. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica 101:1343–50
     [Google Scholar]
  59. 59.
    Kocak H, Ballew BJ, Bisht K, Eggebeen R, Hicks BD et al. 2014. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev. 28:2090–102
     [Google Scholar]
  60. 60.
    Lee DD, Komosa M, Nunes NM, Tabori U. 2020. DNA methylation of the TERT promoter and its impact on human cancer. Curr. Opin. Genet. Dev. 60:17–24
     [Google Scholar]
  61. 61.
    Lee HW, Blasco MA, Gottlieb GJ, Horner JW II, Greider CW, DePinho RA. 1998. Essential role of mouse telomerase in highly proliferative organs. Nature 392:569–74
     [Google Scholar]
  62. 62.
    Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. 1992. Telomere end-replication problem and cell aging. J. Mol. Biol. 225:951–60
     [Google Scholar]
  63. 63.
    Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR. 1997. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276:561–67
     [Google Scholar]
  64. 64.
    Maciejowski J, de Lange T. 2017. Telomeres in cancer: tumour suppression and genome instability. Nat. Rev. Mol. Cell Biol. 18:175–86
     [Google Scholar]
  65. 65.
    Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. 2015. Chromothripsis and kataegis induced by telomere crisis. Cell 163:1641–54
     [Google Scholar]
  66. 66.
    McNally EJ, Luncsford PJ, Armanios M. 2019. Long telomeres and cancer risk: the price of cellular immortality. J. Clin. Investig. 129:3474–81
     [Google Scholar]
  67. 67.
    Mitchell JR, Wood E, Collins K 1999. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402:551–55
     [Google Scholar]
  68. 68.
    Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH et al. 1997. Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–59
     [Google Scholar]
  69. 69.
    Nandakumar J, Cech TR. 2013. Finding the end: recruitment of telomerase to telomeres. Nat. Rev. Mol. Cell Biol. 14:69–82
     [Google Scholar]
  70. 70.
    Oseini AM, Hamilton JP, Hammami MB, Kim A, Oshima K et al. 2021. Liver transplantation in short telomere-mediated hepatopulmonary syndrome following bone marrow transplantation using HCV positive allografts: a case series. Liver Transplant 27:1844–48
     [Google Scholar]
  71. 71.
    Parry EM, Alder JK, Lee SS, Phillips JA III, Loyd JE et al. 2011. Decreased dyskerin levels as a mechanism of telomere shortening in X-linked dyskeratosis congenita. J. Med. Genet. 48:327–33
     [Google Scholar]
  72. 72.
    Parry EM, Alder JK, Qi X, Chen JJ, Armanios M. 2011. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117:5607–11
     [Google Scholar]
  73. 73.
    Perera SA, Maser RS, Xia H, McNamara K, Protopopov A et al. 2008. Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer. Carcinogenesis 29:747–53
     [Google Scholar]
  74. 74.
    Podlevsky JD, Bley CJ, Omana RV, Qi X, Chen JJ. 2008. The telomerase database. Nucleic Acids Res. 36:D339–43
     [Google Scholar]
  75. 75.
    Polvi A, Linnankivi T, Kivela T, Herva R, Keating JP et al. 2012. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am. J. Hum. Genet. 90:540–49
     [Google Scholar]
  76. 76.
    Popescu I, Mannem H, Winters SA, Hoji A, Silveira F, McNally E et al. 2019. Impaired cytomegalovirus immunity in idiopathic pulmonary fibrosis lung transplant recipients with short telomeres. Am. J. Respir. Crit. Care Med. 199:362–76
     [Google Scholar]
  77. 77.
    Reilly CR, Myllymaki M, Redd R, Padmanaban S, Karunakaran D et al. 2021. The clinical and functional effects of TERT variants in myelodysplastic syndrome. Blood 138:898–911
     [Google Scholar]
  78. 78.
    Rode L, Nordestgaard BG, Bojesen SE. 2016. Long telomeres and cancer risk among 95 568 individuals from the general population. Int. J. Epidemiol. 45:1634–43
     [Google Scholar]
  79. 79.
    Rudolph KL, Millard M, Bosenberg MW, DePinho RA. 2001. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 28:155–59
     [Google Scholar]
  80. 80.
    Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP. 2008. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82:501–9
     [Google Scholar]
  81. 81.
    Schratz KE, Armanios M. 2020. Cancer and myeloid clonal evolution in the short telomere syndromes. Curr. Opin. Genet. Dev. 60:112–18
     [Google Scholar]
  82. 82.
    Schratz KE, Gaysinskaya V, Cosner ZL, DeBoy EA, Xiang Z et al. 2021. Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders. J. Clin. Investig. 131:e147598
     [Google Scholar]
  83. 83.
    Schratz KE, Haley L, Danoff SK, Blackford A, DeZern A et al. 2020. Cancer spectrum and outcomes in the Mendelian short telomere syndromes. Blood 135:1946–56
     [Google Scholar]
  84. 84.
    Sholes SL, Karimian K, Gershman A, Kelly TJ, Timp W, Greider CW. 2022. Chromosome-specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing. Genome Res. 32:616–28
     [Google Scholar]
  85. 85.
    Silhan LL, Shah PD, Chambers DC, Snyder LD, Riise GC et al. 2014. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. Eur. Respir. J. 44:178–87
     [Google Scholar]
  86. 86.
    Simon AJ, Lev A, Zhang Y, Weiss B, Rylova A et al. 2016. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J. Exp. Med. 213:1429–40
     [Google Scholar]
  87. 87.
    Stanley SE, Armanios M. 2015. The short and long telomere syndromes: paired paradigms for molecular medicine. Curr. Opin. Genet. Dev. 33:1–9
     [Google Scholar]
  88. 88.
    Stanley SE, Chen JJ, Podlevsky JD, Alder JK, Hansel NN et al. 2015. Telomerase mutations in smokers with severe emphysema. J. Clin. Investig. 125:563–70
     [Google Scholar]
  89. 89.
    Stanley SE, Gable DL, Wagner CL, Carlile TM, Hanumanthu VS et al. 2016. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci. Transl. Med. 8:351ra107
     [Google Scholar]
  90. 90.
    Stanley SE, Merck SJ, Armanios M. 2016. Telomerase and the genetics of emphysema susceptibility. Implications for pathogenesis paradigms and patient care. Ann. Am. Thorac. Soc. 13:Suppl. 5S447–51
     [Google Scholar]
  91. 91.
    Stuart BD, Choi J, Zaidi S, Xing C, Holohan B et al. 2015. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat. Genet. 47:512–17
     [Google Scholar]
  92. 92.
    Takai H, Jenkinson E, Kabir S, Babul-Hirji R, Najm-Tehrani N et al. 2016. A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Genes Dev. 30:812–26
     [Google Scholar]
  93. 93.
    Taub MA, Conomos MP, Keener R, Iyer KR, Weinstock JS. 2022. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom. 2:100084
     [Google Scholar]
  94. 94.
    Taylor AMR, Rothblum-Oviatt C, Ellis NA, Hickson ID, Meyer S et al. 2019. Chromosome instability syndromes. Nat. Rev. Dis. Primers 5:64
     [Google Scholar]
  95. 95.
    Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G et al. 2007. Adult-onset pulmonary fibrosis caused by mutations in telomerase. PNAS 104:7552–57
     [Google Scholar]
  96. 96.
    Tummala H, Walne A, Collopy L, Cardoso S, de la Fuente J et al. 2015. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J. Clin. Investig. 125:2151–60
     [Google Scholar]
  97. 97.
    Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M et al. 2008. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. PNAS 105:8073–78
     [Google Scholar]
  98. 98.
    Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M et al. 2001. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413:432–35
     [Google Scholar]
  99. 99.
    Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. 2004. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat. Genet. 36:447–49
     [Google Scholar]
  100. 100.
    Wagner CL, Hanumanthu VS, Talbot CC Jr., Abraham RS, Hamm D et al. 2018. Short telomere syndromes cause a primary T cell immunodeficiency. J. Clin. Investig. 128:5222–34
     [Google Scholar]
  101. 101.
    Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M et al. 2007. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Mol. Genet. 16:1619–29
     [Google Scholar]
  102. 102.
    Wang Y, Liyanarachchi S, Miller KE, Nieminen TT, Comiskey DF Jr. et al. 2019. Identification of rare variants predisposing to thyroid cancer. Thyroid 29:946–55
     [Google Scholar]
  103. 103.
    Wong K, Robles-Espinoza CD, Rodriguez D, Rudat SS, Puig S. 2019. Association of the POT1 germline missense variant p.I78T with familial melanoma. JAMA Dermatol. 155:604–9
     [Google Scholar]
  104. 104.
    Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR et al. 2003. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421:643–48
     [Google Scholar]
  105. 105.
    Xi L, Cech TR. 2014. Inventory of telomerase components in human cells reveals multiple subpopulations of hTR and hTERT. Nucleic Acids Res. 42:8565–77
     [Google Scholar]
  106. 106.
    Zhong F, Savage SA, Shkreli M, Giri N, Jessop L et al. 2011. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25:11–16
     [Google Scholar]
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The Role of Telomeres in Human Disease
Annual Review of Genomics and Human Genetics 23, 363 (2022); https://doi.org/10.1146/annurev-genom-010422-091101
/content/journals/10.1146/annurev-genom-010422-091101
/content/journals/10.1146/annurev-genom-010422-091101
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