Haploinsufficiency of t e lomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita
Open accessAbstract
Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenita display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.
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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.”
From The telomere syndromes (2012) · cites this paper as [39]
Families carrying mutant telomerase genes show genetic anticipation.
“The most compelling evidence for the causal role of telomere shortening as a primary modifier of disease is that families with mutant telomerase genes display genetic anticipation39,83.”
From The telomere syndromes (2012) · cites this paper as [39]
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).”
From The telomere syndromes (2012) · cites this paper as [39]
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.”
From The telomere syndromes (2012) · cites this paper as [39]
Even when one disorder's symptoms dominate, affected people often have subclinical disease in other organs at the same time.
“However, affected individuals often have subclinical disease concurrently in other organs, even when symptoms related to a single disorder predominate13,39.”
From The telomere syndromes (2012) · cites this paper as [39]
TERT was considered a candidate because a mutation in this gene was recently reported to cause autosomal dominant dyskeratosis congenita (DKC), a disorder in which 20% of affected individuals develop pulmonary fibrosis.
“Among the genes we evaluated was TERT, which was considered a candidate because a mutation in this gene was recently reported to cause autosomal dominant dyskeratosis congenita (DKC), a disorder in which 20% of affected individuals develop pulmonary fibrosis (6, 7).”
From Adult-onset pulmonary fibrosis caused by mutations in telomerase (2007) · cites this paper as [6]
Telomere length is influenced by many different factors, including age and the number of generations the mutation is transmitted.
“Telomere length is influenced by many different factors, including age (13, 14) and the number of generations the mutation is transmitted (6, 15).”
From Adult-onset pulmonary fibrosis caused by mutations in telomerase (2007) · cites this paper as [6]
Individuals with TERT or TERC mutations have none of the physical manifestations of DKC and were all ascertained by the lung fibrosis phenotype, distinguishing them from previously described patients with mutations in these genes.
“The individuals with TERT or TERC mutations have none of the physical manifestations of DKC and were all ascertained by the lung fibrosis phenotype, distinguishing them from previously described patients with mutations in these genes (6, 9, 10, 17).”
From Adult-onset pulmonary fibrosis caused by mutations in telomerase (2007) · cites this paper as [6]
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- Authors
- Armanios, M., Chen, J.-L., Chang, Y.-P. C., Brodsky, R. A., Hawkins, A., Griffin, C. A., Eshleman, J. R., Cohen, A. R., Chakravarti, A., Hamosh, A., & Greider, C. W.
- Affiliations
- Children's Hospital of Philadelphia (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-10-24
- Volume
- 102
- Issue
- 44
- Pages
- 15960-15964
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1276104
- OpenAlex
- W1985641439
- Cited by
- 452
- References
- 29
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 14 · 2023: 17 · 2022: 15 · 2021: 17 · 2020: 28 · 2019: 20 · 2018: 16 · 2017: 12 · 2016: 20 · 2015: 20 · 2014: 29 · 2013: 27 · 2012: 20
- FWCI
- 15.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Association for Cancer Research
- Amgen
- National Cancer Institute (P01CA016519)
- 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 › Genetics › Genetic and rare skin diseases.
- Keywords
- dyskeratosis congenita, telomerase reverse transcriptase, hTERT, haploinsufficiency, anticipation, autosomal dominant inheritance, telomere shortening, telomerase RNA, null mutations, telomere maintenance, bone marrow failure, cancer susceptibility, idiopathic pulmonary fibrosis, pedigree analysis
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Family Health, Female, Genes, Dominant, Haplotypes, Humans, Male, Middle Aged, Mutation, Pedigree, Phenotype, Telomere, Gene Dosage, Telomerase, Dyskeratosis Congenita, Anticipation, Genetic, Cell Proliferation
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