Genes Encoding Telomere-Binding Proteins TERF1, TERF2 and TIN2 Are mutated in Patients with Acquired Aplastic Anemia.
Notice bibliographique
Résumé
Abstract Telomere shortening is observed in some patients with acquired aplastic anemia (AA) and associates with poor response to immunosuppressive therapy. Mutations in components of the telomerase complex (RNA component, TERC, and reverse transcriptase, TERT) have been found in AA patients. As the proportion of AA patients with short telomeres is greater than the number of patients with telomerase complex component mutations, we investigated whether genetic variations in the telomere-binding proteins telomeric repeat binding factor 1 (TERF1), telomeric repeat binding factor 2 (TERF2) and TERF1-interacting nuclear factor 2 (TIN2) were also associated with AA. TERF1 is a negative regulator of telomere length; TIN2 regulates TERF1 function, and TERF2 protects telomeres from degradation and fusion. Bi-directional sequence analysis was performed across all exons and proximal promoter regions of TERF1, TERF2, and TINF2 genes in 147 patients with AA and 118 healthy subjects. Haplotypes were inferred by Phase 2.0. Telomere length of leukocytes was measured by flow cytometry fluorescent in situ hybridization (flow-FISH). A nonsynonymous mutation in TERF1, exon 9, codon 377 (Ala → Val) was found in a 15-year old African-American girl who did not respond to immunosuppressive therapy, but not in controls. A specific TERF1 haplotype was more common in patients (P=0.004), whereas another haplotype was more common in controls (P=0.02). For TERF2 , a mutation in exon 6, codon 273 (Ala→Ser) was found in a 40 year-old Caucasian female patient, but not in controls. A G/A single nucleotide polymorphism (SNP) in exon 6 was present in 15% of patients and 9% of controls (P=0.04). TINF2 was the most polymorphic gene in both patients and contorls. As these variants were found mainly in African-Americans, additional 94 healthy African-American controls were sequenced. In the proximal promoter region, two SNPs and one 16-base-pair deletion were found in patients, but not in 212 controls. The 16-base-pair deletion (−10 to −25) was found in a 31-year-old African-American female who did not respond to immunosuppression, with very short telomeres of leukocytes (Δ TRF −2.59 kb). Also, a -97G/C transition was found in a 66-year-old African-American female who partially responded to immunosupression, also tracking to short telomeres (ΔTRF, −1.22 kb). The −260G/C promoter SNP was present in 3.5% of controls and 0.4% of patients P<0.0001), and the −91C/T SNP was seen in 1.7% of controls but not in patients (P<0.0001). The most common haplotype was seen in 94% of patients and 86% of controls (P=0.003), suggesting an at risk haplotype. A rare haplotype in patients (0.4%) was more common in controls, 3.4% (P=0.01) suggesting a rare but potentially protective variant. These data suggest that mutations and specific haplotypes may confer risk for AA. In addition, we have identified novel mutations in three genes that are essential for telomere stability. In conclusion, mutations in different genes involved in telomere stability and repair appear to be hematologic genetic risk factors for bone marrow failure in adults.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».