Characterization of Novel Natural Mutations in Telomere Binding Protein Factor (TIN2) Identified in Patients with Bone-Marrow Failure Syndromes
Bibliographic record
Abstract
Abstract We report for the first time potential pathogenic mutations in a known telomeric DNA binding protein factor (TIN2) in patients with acquired aplastic anemia. We examined samples collected from 142 AA patients and 289 healthy controls and found several natural sequence changes in the TINF2 gene, which encodes for the TIN2 protein. Lymphocytes collected from patients with TINF2 variant alleles appeared to grow slower in culture than cells collected from either healthy individuals or those who carried inconsequential polymorphic TINF2 sequence changes (SNPs), consistent with the fact that telomere lengths in these patients were shorter than those of healthy individuals of similar age. We introduced natural mutations in the TIN2 promoter region into a TIN2-promoter driven luciferase reporter plasmid and examined their effect on driving luciferase reporter expression. Using a similar approach, we defined both the regulatory DNA elements and transcriptional factors that control TINF2 gene expression under normal physiological condition. Results obtained from these studies were validated in gel-shift (EMSA) and chromatin immunoprecipitation (ChIP) assays. In addition to mutations in the promoter region, numerous natural mutations were identified in the coding region of the TINF2 gene in patients with AA or Dyskeratosis Congenita (DC). We used co-immunoprecipitation assays to test the effect of natural mutations in disrupting TIN2’s interaction with its known protein partners TRF1, TRF2 and TPP1 of the shelterin complex that protects chromosome ends. The results obtained from these studies will be discussed. To our knowledge, this is the first comprehensive functional analysis of all known mutations in the TINF2 gene in patients with AA or DC. This study offers an insight into how TINF2 mutations can lead to telomere shortening effect and to limited marrow stem-cell reserve and renewal capacity in patients with various forms of bone-marrow failure syndromes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".