Dyskeratosis Congenita - A Disease of Dysfunctional Telomere Maintenance
Abstract
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome associated with abnormalities of the skin, fingernails, and tongue. Other clinical manifestations may include epiphora, lung fibrosis, liver cirrhosis, osteoporosis, and a predisposition to develop a variety of malignancies. The clinical picture often resembles that of a premature aging syndrome and tissues affected are those with a high cell turnover. DC has been linked to mutations in at least four distinct genes, three of which have been identified. The product of these genes, dyskerin, the telomerase RNA (TERC), and the catalytic unit of telomerase (TERT) are part of a ribonucleoprotein complex, the telomerase enzyme, that is essential for the elongation and maintenance of chromosome ends or telomeres. All patients with DC have excessively short telomeres, indicating that the underlying defect in these individuals is an inability to maintain the telomeres. The purpose of the current review is to highlight recent insights into the molecular pathogenesis of DC. We discuss the impact these findings have on our current understanding of telomere function and maintenance, and on the diagnosis, management, and treatment of patients with conditions caused by dysfunctional telomeres.
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Patients with dyskeratosis congenita and aplastic anaemia show decreased telomerase activity and shortened telomeres owing to mutations in the TERC and TERT telomerase genes.
“By contrast, telomere shortening is accelerated in several human premature ageing syndromes, and patients with dyskeratosis congenita and aplastic anaemia show decreased telomerase activity and shortened telomeres owing to mutations in the TERC and TERT telomerase genes.”
From The common biology of cancer and ageing (2007) · cites this paper as [64]
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Hosseinverdi, S., Hashemi, H., Aghamohammadi, A., Ochs, H. D., & Rezaei, N. (2013) · Journal of Clinical Immunology · doi:10.1007/s10875-013-9974-2 · Cited by 17 · see citing works
“A common feature of DC is defective telomere maintenance which places affected patients at a significant risk for developing malignancies and premature aging [170].”
BackgroundPROLIFERATIVE RETINOPATHY AS A COMPLICATION OF DYSKERATOSIS CONGENITA
Mason, J. O., Yunker, J. J., Nixon, P. A., Vail, R. S., Tsilou, E., Giri, N., & Alter, B. P. (2009) · Retinal Cases & Brief Reports · doi:10.1097/01.icb.0000315662.87050.bf · Cited by 17 · see citing works
Dyskeratosis congenita with corneal limbal insufficiency
Aslan, D., Özdek, Ş. C., Camurdan, O. M., Bıdecı, A., & Cınaz, P. (2009) · Pediatric Blood & Cancer · doi:10.1002/pbc.21960 · Cited by 16 · see citing works
Telomere replication: poised but puzzling
Sampathi, S., & Chai, W. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01220.x · Cited by 15 · see citing works
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Telomere length as a predictive biomarker in osteoporosis (Review)
Kakridonis, F., Pneumatikos, S. G., Vakonaki, E., Berdiaki, A., Tzatzarakis, M. N., Fragkiadaki, P., Spandidos, D. A., Baliou, S., Ιωάννου, Π., Hatzidaki, E., et al. (2023) · Biomedical Reports · doi:10.3892/br.2023.1669 · Cited by 15 · see citing works
“In the aforementioned genetic disorders, osteo‑ porosis is accomplished to a greater extent than that achieved with natural aging, and the distribution of included osteoporosis in WS appears at the limbs more than the axial skeleton (78,79).”
BackgroundMaillet, F., Galimard, J., Borie, R., Lainey, É., Larcher, L., Passet, M., Plessier, A., Leblanc, T. M., Terriou, L., Lebon, D., et al. (2024) · British Journal of Haematology · doi:10.1111/bjh.19767 · Cited by 13 · see citing works
“2,8,9 10–16 The true prevalence of TBD is currently unknown and probably underestimated because of its clinical heterogeneity, variable age at disease onset and incomplete penetrance.”
Genetics of proliferative aging
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“…the related disease aplastic anemia also have mutations in components of telomerase and display unusually short telomeres that may cause proliferative defects of the lymphatic system in middle age, in addition to less penetrant phenotypes such as brittle hair or skin spots (Mason et al., 2005).”
InfluentialMakarova, J. A., & Kramerov, D. A. (2007) · Molecular Biology · doi:10.1134/s0026893307020045 · Cited by 11 · see citing works
“Some mutations of the dyskerin gene cause dyskeratosis congenital, a hereditary disorder that is accompanied by poikiloderma (dystrophic changes in the skin), nail dystrophy, and several other signs [46].”
BackgroundPignolo, R. J., & Chandra, A. (2025) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2025.112025 · Cited by 10 · see citing works
Measuring Telomere Length—From Ends to Means
Petkova, R., Chicheva, Z., & Chakarov, S. (2011) · Biotechnology & Biotechnological Equipment · doi:10.5504/bbeq.2011.0103 · Cited by 8 · see citing works
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“The latter 4 proteins are also associated with telomerase RNA, which contains an H/ACA domain [4],[5], and mutations in the gene encoding dyskerin are responsible for X-linked dyskeratosis congenita, a disease whose major cause is defective telomere maintenance [6].”
Self-citationSkeletal phenotypes and molecular mechanisms in aging mice
Guan, Q., 上海体育大学运动健康学院, 上. 2., Zhang, Y., Wang, Z., Liu, X.-H., Zou, J., & Zhang, L.-L. (2024) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2023.397 · Cited by 11 · see citing works
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Structure–function relationships of archaeal Cbf5 during in vivo RNA-guided pseudouridylation
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“Mutations of HvCbf5 corresponding to DKC1 mutations causing dyskeratosis congenita do not abolish Ψ modification Mutations of DKC1 that cause DC are well dispersed on the dyskerin structure (Mason et al. 2005).”
BackgroundMechanisms of Disordered Granulopoiesis in Congenital Neutropenia
Grenda, D. S., & Link, D. C. (2006) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)74005-4 · Cited by 6 · see citing works
Perona, R. (2010) · Clinical & Translational Oncology · doi:10.1007/s12094-010-0572-y · Cited by 5 · see citing works
“Mutations in either hTR or hTERT, or other components of the telomerase complex, such as dyskerin, Nola2 and Nola3, have been found in these groups of patients [ 23 , 25].”
BackgroundTelomerase as a Target for Cancer Therapeutics
Shay, J. W. (2010) · Springer eBooks · doi:10.1007/978-1-4419-6102-0_13 · Cited by 8 · see citing works
Telomere and Telomerase for the Regulation of Stem Cells
Hiyama, E., & Hiyama, K. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-227-8_11 · Cited by 4 · see citing works
“The diseases due to deficiency in telomerase activity and short telomeres are characterized by skin abnormalities and bone marrow failure, the latter resulting from defects in maintaining the hematopoietic stem cell compartment [60, 79, 80].”
BackgroundInfluentialIdentification of a novel mutation in DKC1 in dyskeratosis congenita
Kurnikova, M. A., Shagina, I. A., Khachatryan, L., Shchagina, O., Maschan, M. A., & Shagin, D. A. (2008) · Pediatric Blood & Cancer · doi:10.1002/pbc.21733 · Cited by 4 · see citing works
“The hypothesis that DC is primarily a disorder of telomere maintenance is strengthened by the discovery that the telomerase RNA component (TERC) and the enzymatic component (TERT) of telomerase [6], telomerase-associated protein NOP10 [7] and the recently discovered TINF2, a component of the shelterin telomere protect…”
BackgroundCell-cycle-dependent telomere elongation by telomerase in budding yeast
Li, S. (2011) · Bioscience Reports · doi:10.1042/bsr20100095 · Cited by 4 · see citing works
Human Mutations Affecting Reprogramming into Induced Pluripotent Stem Cells
Hayashi, Y. (2017) · AIMS Cell and Tissue Engineering · doi:10.3934/celltissue.2017.1.31 · Cited by 4 · see citing works
“Dyskeratosis congenita (DC; OMIM #305000) is characterized by the defective maintenance of blood, pulmonary and epidermal tissues [62,63].”
Sáez‐de‐Ocariz, M., Orozco‐Covarrubias, L., Durán‐McKinster, C., & Ruiz‐Maldonado, R. (2008) · Springer eBooks · doi:10.1007/978-3-211-69500-5_44 · Cited by 3 · see citing works
- Authors
- Mason, P., Wilson, D., & Bessler, M.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Wilson, D.
- Venue
- Current Molecular Medicine
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2005-03-01
- Volume
- 5
- Issue
- 2
- Pages
- 159-170
- ISSN
- 1566-5240 (ISSN-L)
- OpenAlex
- W2110736059
- Cited by
- 129
- References
- 0
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 9 · 2013: 5 · 2012: 9
- FWCI
- 10.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA105312, CA105312-01)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- dyskeratosis congenita, telomere maintenance, telomerase, dyskerin, telomerase reverse transcriptase (TERT), bone marrow failure, premature aging, genetic disorders, molecular pathogenesis, telomere dysfunction, cancer susceptibility, pulmonary fibrosis, liver cirrhosis
- MeSH terms
- Humans, Mutation, Neoplasms, Genetic Therapy, Telomere, Telomerase, Dyskeratosis Congenita, Genetic Predisposition to Disease, Chromosomes, Human, X
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