SEARCH · PubMed Health

Results for “Telomerase”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

30 records · Page 2Linked to original sources

PubMed2026

Genomic and computational analysis of variants in telomere regulatory genes in subjects with bone marrow failure.

Telomere Biology Disorders (TBDs) are a genetically heterogeneous and often under-recognized cause of Bone Marrow Failure Syndromes (BMFS), driven by defective telomere maintenance and progressive telomere attrition. We performed an integrated genomic, telomeric and computational analysis in 118 subjects presenting clinical features of BMFS to delineate the contribution of Telomere Regulatory Genes (TRGs) variants to disease pathogenesis. Whole exome sequencing (WES) identified pathogenic (18.18%), likely pathogenic (27.27%) and rare variants of uncertain significance (54.54%) in 27 subjects (22.9%) across five TRGs: RTEL1, TERT, TINF2, NOP10, and WRAP53. Telomere Length (TL) assessment revealed significant telomere shortening in TRG variant-positive subjects compared with age-matched controls, with the most profound attrition observed in individuals harboring de novo TINF2 gene variants. RTEL1 emerged as the most frequently affected gene, with recurrent clustering of variants within its C-terminal regulatory region. A familial NOP10 variant, Asp12His, segregated with cutaneous pigmentation and hematological abnormalities consistent with the established role of NOP10 in dyskeratosis congenita, further broadening the known mutational spectrum of the gene. Structure-guided in-silico analyses predicted that both novel and recurrent variants disrupt protein stability, telomerase assembly or trafficking and shelterin complex integrity. Reduced TERT expression and a significant inverse correlation between telomere length and clinical severity further underscored the functional impact of TRG defects. Collectively, this study provides the first comprehensive characterization of TRG variants in the Indian BMFS cohort and highlights the utility of integrating genomic sequencing, telomere length measurement and computational modeling to improve diagnostic precision, variant interpretation and clinical stratification in TBDs.

Journal Article↗

PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗

PubMed2026

Convergence and conflict among telomere-specialized transposons across 60 million years of Drosophilid evolution.

The Drosophila telomere is one of the best-studied examples of active transposable elements (TEs) benefiting, rather than harming, the host genome. All Drosophila species lack telomerase, and most species instead have telomeres composed of head-to-tail arrays of specialized retrotransposons. These TEs ostensibly act as mutualists by elongating chromosome ends, but evidence from species closely related to Drosophila melanogaster suggests that telomeric transposons may also antagonize their host genome. Importantly, the limited number of Drosophila species characterized thus far has precluded our ability to delineate idiosyncrasies from universal evolutionary forces and genetic mechanisms that shape the history of these TEs. Here, we have surveyed long-read genome assemblies of more than 100 species of Drosophila, identifying a total of 396 telomeric TE families. Our findings show that these telomere-specialized elements evolve dynamically and also undergo striking convergent evolution: The complete loss of telomeric TEs has occurred repeatedly across the genus, whereas individual telomeric TE lineages have repeatedly lost one of their two protein-coding genes. These elements have also repeatedly undergone horizontal transfer between distantly related Drosophila lineages and have repeatedly captured host gene fragments that promote their selfish suppression of host TE-silencing systems. Furthermore, telomere specialization itself appears to have evolved convergently, as some nontelomeric families have gained the ability to target their insertions to telomeres. These results provide unprecedented resolution into the evolution of these unusual TEs and highlight several novel mechanisms by which they evolve in conflict both with each other and their host genome despite the essential telomere function they provide.

Animals↗

PubMed2026

Establishment of Stable Immortalized Human Choroidal Melanocytes for Ocular Research.

PURPOSE: The short lifespan of primary normal choroidal melanocytes (NCMs) in vitro represents a major barrier to mechanistic, functional, and translational studies of choroid biology and uveal melanoma (UM). This study aimed to establish and characterize immortalized human NCM lines that retain melanocytic function, maintain a non-cancerous profile, and are amenable to gene editing. METHODS: NCMs from four donors were immortalized by lentiviral transduction of cyclin-dependent kinase 4 (CDK4R24C), cyclin D1, and human telomerase reverse transcriptase (hTERT), establishing NCM-K4DT lines. Their morphology, melanocytic marker expression, proliferation, and functional properties (melanin synthesis and tyrosinase activity) were evaluated. Genomic stability was assessed by targeted mutation profiling, karyotyping, and copy number variation (CNV) analysis. The tumorigenicity was tested in immunodeficient mice. Plasmid-based CRISPR/Cas9 editing was performed to determine their suitability for gene editing. RESULTS: NCM-K4DT lines retained dendritic-shaped morphology, pigmentation, and expression of PMEL, TYRP1, Melan-A, and SOX10. Cells exhibited enhanced proliferative capacity with preserved cell cycle regulation. Melanin production and tyrosinase activity were comparable to primary NCMs. Genomic profiling confirmed the absence of UM-associated driver mutations and chromosomal abnormalities. In vivo growth assays demonstrated that NCM-K4DT lines did not form tumors within the 3-month observation period. Notably, NCM-K4DT cells were efficiently edited by CRISPR/Cas9. CONCLUSIONS: NCM-K4DT lines represent stable, non-cancerous, and genetically tractable models for studying choroidal melanocyte biology, modeling UM-associated mechanisms, and advancing therapeutic development in ocular research.

Humans↗

PubMed2026

Cytologic and Surgical Correlation of TERT-Mutated Indeterminate Thyroid Nodules: A Case Series.

IntroductionTelomerase reverse transcriptase (TERT) promoter mutations is a relatively novel mutation that has been linked with thyroid cancers. This study examines the frequency, cytology and histo-morphologic features, and clinical outcomes of TERT-mutated indeterminate thyroid nodules.MethodsA retrospective review of Bethesda III and IV thyroid cytology specimen sent for ThyroSeq® testing (2019-2022) was performed, selecting those with TERT mutations. Demographics, cytologic features, surgical diagnoses, and follow-up data were analyzed.ResultsAmong 567 specimens tested, 12 (2%) harbored TERT mutations; 4 had TERT alone, and 8 had additional mutations. Average age of patients was 69 years (92% > 50 years). Eight had surgical follow-up: 50% were malignant, 25% were benign and 25% were of uncertain malignant potential. Additionally, 62% were oncocytic nodules. Clinical follow-up showed all evaluated patients were alive without recurrences or metastases at last contact.ConclusionIn our cohort, TERT promoter mutations were rare in indeterminate thyroid nodules (2%) and frequently accompanied by additional molecular changes. It is more frequently detected in older patients. Unlike prior reports describing TERT mutations exclusively in malignant thyroid tumors, our findings encompassed a broader histological spectrum, including benign, uncertain malignant potential and malignant lesions.

Humans↗

PubMed2026

Clinical performance of the urine-based TERT promoter AbsoluteQ Digital PCR for non-invasive detection of bladder cancer.

Bladder cancer (BC) is the ninth most common cancer worldwide, with urothelial carcinoma accounting for approximately 90% of all cases and presenting predominantly as non-muscle-invasive disease. Due to its high recurrence rate and the need for long-term surveillance, BC is associated with the highest lifetime treatment costs per patient among all cancers, making its effective management a significant clinical and economic challenge. The most frequently identified variants in the TERT gene promoter are c.-124C>T (C228T) and c.-146C>T (C250T), located within a region characterized by high guanine-cytosine (GC) content, which makes amplification challenging. We aimed to validate the AbsoluteQ Digital PCR assay for the detection of urine-based TERT promoter variants for the diagnosis of urothelial bladder cancer and to assess its diagnostic performance in comparison with standard methods. Urine samples were collected from patients with histopathologically confirmed bladder cancer (n = 58) and compared with a control group (n = 55). The C228T and C250T variants were tested using the AbsoluteQ Digital PCR assay. Sensitivity, specificity, and predictive values were calculated to evaluate the performance of the assessed method. The AbsoluteQ Digital PCR demonstrated superior diagnostic performance compared to conventional Sanger sequencing for detecting TERT promoter variants, achieving a sensitivity of 89.65% (95% CI: 78.16-95.72) and a specificity of 100% (95% CI: 91.87-100), with no false positives observed. Given its robustness and clinical relevance, AbsoluteQ Digital PCR is emerging as a promising tool for non-invasive molecular diagnostics targeting TERT promoter variants.

Humans↗

PubMed2026

Active Site Assembly by SMG5 as a Mechanism for SMG6 Endonuclease Licencing in Nonsense-mediated mRNA Decay.

Nonsense-mediated mRNA decay (NMD) is a conserved eukaryotic surveillance pathway that eliminates transcripts containing premature termination codons (PTCs). Substantial progress has been made in defining the transcript features that mark aberrant translation termination for NMD activation, yet key mechanistic steps remain incompletely understood - including how recruitment of the central NMD factor UPF1 is coupled to the downstream effector phase in which targeted mRNAs are nucleolytically degraded. In metazoans, NMD employs an endonucleolytic route mediated by SMG6, a PIN-domain nuclease, alongside SMG5 and SMG7, which act downstream of PTC recognition. SMG5 has recently been proposed to licence SMG6 activity, yet the molecular basis of this licencing has remained elusive. Here, we combine AlphaFold structural predictions with biochemical assays to investigate interactions among human SMG5, SMG6, and SMG7. Structural models predict a high-confidence interface between SMG5 and SMG6 PIN domains that forms a composite active site: a conserved SMG5 aspartate (D893) complements the SMG6 acidic triad to reinstate the canonical tetrad required for PIN-domain catalysis. In vitro, SMG6 alone exhibits weak endonucleolytic activity, which is enhanced ∼10-fold by the SMG5 PIN domain. Mutational analyses confirm that conserved residues from both proteins are essential for this composite configuration. Our findings reveal that the SMG5 PIN domain, previously considered catalytically inert, plays a critical role in activating SMG6 by completing its active site. This work provides mechanistic insight into the SMG5-dependent licencing step and uncovers a composite PIN nuclease architecture at the heart of the metazoan NMD effector phase.

Nonsense Mediated mRNA Decay↗

PubMed2026

Investigating telomere length and hTERT-MNS16A VNTR polymorphism in Bipolar disorder: Insights into clinical features.

OBJECTIVE: To compare leukocyte telomere length (LTL; T/S ratio) and hTERT-MNS16A VNTR polymorphism between patients with bipolar disorder (BD) and healthy controls, and to examine their associations with clinical features in BD. METHODS: A total of 179 participants (100 BD patients, 79 healthy controls) were enrolled. Relative LTL was assessed by qPCR-based T/S ratio; hTERT-MNS16A VNTR genotyping by PCR and gel electrophoresis. Clinical variables including episode frequency, illness duration, age at onset, symptom severity scales, first episode polarity, and family history of mood disorder were evaluated. RESULTS: No significant differences were observed between BD patients and healthy controls in T/S ratio or hTERT-MNS16A VNTR genotype distributions (all p > 0.05). Within the BD group, S allele carriers (L/S or S/S) had significantly more depressive episodes than L/L homozygotes (1.45 ± 2.58 vs. 0.61 ± 1.52; p = .040). Significant inverse correlations were identified between T/S ratio and depressive episode count (ρ = -0.220, p = .028) and total mood episodes (ρ = -0.207, p = .039). Multivariable negative binomial regression revealed four independent predictors of depressive episode frequency: lower T/S ratio (p = 0.005), S allele carriage (L/S or S/S genotypes) (p = 0.001), first depressive episode polarity (p < 0.001), and family history of mood disorder (p = 0.035). CONCLUSION: Although LTL and hTERT-MNS16A VNTR genotype did not differ between BD patients and healthy controls, shorter telomere length and S allele carriage were independently associated with higher depressive episode frequency within the BD group, implicating telomere biology and hTERT genetic variation in the biological substrate of depressive illness burden.

Humans↗

PubMed2025

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

BACKGROUND: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS: We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS: 64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION: The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

Humans↗

PubMed2026

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

Humans↗

PubMed2024

Comparative genomic landscape of lower-grade glioma and glioblastoma.

Biomarkers for classifying and grading gliomas have been extensively explored, whereas populations in public databases were mostly Western/European. Based on public databases cannot accurately represent Chinese population. To identify molecular characteristics associated with clinical outcomes of lower-grade glioma (LGG) and glioblastoma (GBM) in the Chinese population, we performed whole-exome sequencing (WES) in 16 LGG and 35 GBM tumor tissues. TP53 (36/51), TERT (31/51), ATRX (16/51), EFGLAM (14/51), and IDH1 (13/51) were the most common genes harboring mutations. IDH1 mutation (c.G395A; p.R132H) was significantly enriched in LGG, whereas PCDHGA10 mutation (c.A265G; p.I89V) in GBM. IDH1-wildtype and PCDHGA10 mutation were significantly related to poor prognosis. IDH1 is an important biomarker in gliomas, whereas PCDHGA10 mutation has not been reported to correlate with gliomas. Different copy number variations (CNVs) and oncogenic signaling pathways were identified between LGG and GBM. Differential genomic landscapes between LGG and GBM were revealed in the Chinese population, and PCDHGA10, for the first time, was identified as the prognostic factor of gliomas. Our results might provide a basis for molecular classification and identification of diagnostic biomarkers and even potential therapeutic targets for gliomas.

Humans↗

PubMed2025

Effect of Physical Exercise on Telomere Length: Umbrella Review and Meta-Analysis.

BACKGROUND: Telomere length (TL) is a marker of cellular health and aging. Physical exercise has been associated with longer telomeres and, therefore, healthier aging. However, results supporting such effects vary across studies. Our aim was to synthesize existing evidence on the effect of different modalities and durations of physical exercise on TL. OBJECTIVE: The aim of this study was to explore the needs and expectations of individuals with physical disabilities and their interventionists for the use of a virtual reality physical activity platform in a community organization. METHODS: We performed an umbrella review and meta-analysis. Data sources included PubMed, Embase, Web of Science, Cochrane Library, and Scopus. We selected systematic reviews and meta-analyses of randomized and nonrandomized controlled clinical trials evaluating the effect of physical exercise on TL. RESULTS: Our literature search retrieved 12 eligible systematic reviews, 5 of which included meta-analyses. We identified 22 distinct primary studies to estimate the overall effect size of physical exercise on TL. The overall effect size was 0.28 (95% CI 0.118-0.439), with a heterogeneity test value Q of 43.08 (P=.003) and I² coefficient of 51%. The number of weeks of intervention explained part of this heterogeneity (Q_B=8.25; P=.004), with higher effect sizes found in studies with an intervention of less than 30 weeks. Exercise modality explained additional heterogeneity within this subgroup (Q_B=10.28, P=.02). The effect sizes were small for aerobic exercise and endurance training, and moderate for high-intensity interval training. CONCLUSIONS: Our umbrella review and meta-analysis detected a small-moderate positive effect of physical exercise on TL, which seems to be influenced by the duration and type of physical exercise. High quality studies looking into the impact of standardized, evidence-based physical exercise programs on TL are still warranted.

Humans↗