ArticleGenes & development2014
A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice.
Article in Genes & development, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 57 citations in OpenAlex.
- Biogenesis and Regulation of Telomerase during Development and Cancer.Cold Spring Harbor perspectives in biology · 2026Review
- C-Terminal Extended Domain-Independent Telomere Maintenance: Modeling the Function of TIN2 Isoforms inInternational journal of molecular sciences · 2025Article
- POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis.Communications biology · 2023Article
- A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing.Iranian biomedical journal · 2023Article
- NovelWorld journal of clinical cases · 2022Article
- Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.Stem cell reviews and reports · 2022Review
- Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita.Blood · 2022Article
- A Rare HeterozygousFrontiers in genetics · 2022Article
- Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline.Life science alliance · 2022Article
- Review
- Shelterin complex gene: Prognosis and therapeutic vulnerability in cancer.Biochemistry and biophysics reports · 2021Review
- TPP1 mutagenesis screens unravel shelterin interfaces and functions in hematopoiesis.JCI insight · 2021Article
- Naked mole rat TRF1 safeguards glycolytic capacity and telomere replication under low oxygen.Science advances · 2021Article
- Regulation of human telomerase in homeostasis and disease.Nature reviews. Molecular cell biology · 2020Review
- Review
- Shelterin Complex at Telomeres: Implications in Ageing.Clinical interventions in aging · 2020Review
- TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity.Molecular and cellular biology · 2019Article
- A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.Neoplasia (New York, N.Y.) · 2019Article
- The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.European journal of human genetics : EJHG · 2019Article
- Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The progressive bone marrow failure syndrome dyskeratosis congenita (DC) is often caused by mutations in telomerase or the factors involved in telomerase biogenesis and trafficking. However, a subset of DC patients is heterozygous for mutations in the shelterin component TIN2. To determine how the TIN2-DC mutations affect telomere function, we generated mice with the equivalent of the TIN2 K280E DC allele (TIN2(DC)) by gene targeting. Whereas homozygous TIN2(DC/DC) mice were not viable, first-generation TIN2(+/DC) mice were healthy and fertile. In the second and third generations, the TIN2(+/DC) mice developed mild pancytopenia, consistent with hematopoietic dysfunction in DC, as well as diminished fecundity. Bone marrow telomeres of TIN2(+/DC) mice shortened over the generations, and immortalized TIN2(+/DC) mouse embryonic fibroblasts (MEFs) showed telomere shortening with proliferation. Unexpectedly, telomere shortening was accelerated in TIN2(+/DC) mTR(-/-) mice and MEFs compared with TIN2(+/+) mTR(-/-) controls, establishing that the TIN2(DC) telomere maintenance defect was not solely due to diminished telomerase action. The TIN2(DC) allele induced mild ATR kinase signaling at telomeres and a fragile telomere phenotype, suggestive of telomere replication problems. These data suggest that this TIN2-DC mutation could induce telomeric dysfunction phenotypes in telomerase-negative somatic cells and tissues that further exacerbate the telomere maintenance problems in telomerase-positive stem cell compartments.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.