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Human Molecular Genetics Mar 2024Telomeres are nucleoprotein structures that protect the chromosome ends from degradation and fusion. Telomerase is a ribonucleoprotein complex essential to maintain the...
Telomeres are nucleoprotein structures that protect the chromosome ends from degradation and fusion. Telomerase is a ribonucleoprotein complex essential to maintain the length of telomeres. Germline defects that lead to short and/or dysfunctional telomeres cause telomere biology disorders (TBDs), a group of rare and heterogeneous Mendelian diseases including pulmonary fibrosis, dyskeratosis congenita, and Høyeraal-Hreidarsson syndrome. TPP1, a telomeric factor encoded by the gene ACD, recruits telomerase at telomere and stimulates its activity via its TEL-patch domain that directly interacts with TERT, the catalytic subunit of telomerase. TBDs due to TPP1 deficiency have been reported only in 11 individuals. We here report four unrelated individuals with a wide spectrum of TBD manifestations carrying either heterozygous or homozygous ACD variants consisting in the recurrent and previously described in-frame deletion of K170 (K170∆) and three novel missense mutations G179D, L184R, and E215V. Structural and functional analyses demonstrated that the four variants affect the TEL-patch domain of TPP1 and impair telomerase activity. In addition, we identified in the ACD gene several motifs associated with small deletion hotspots that could explain the recurrence of the K170∆ mutation. Finally, we detected in a subset of blood cells from one patient, a somatic TERT promoter-activating mutation that likely provides a selective advantage over non-modified cells, a phenomenon known as indirect somatic genetic rescue. Together, our results broaden the genetic and clinical spectrum of TPP1 deficiency and specify new residues in the TEL-patch domain that are crucial for length maintenance and stability of human telomeres in vivo.
Topics: Humans; Biology; Mutation; Shelterin Complex; Telomerase; Telomere; Telomere-Binding Proteins
PubMed: 38176734
DOI: 10.1093/hmg/ddad210 -
Cureus Nov 2023Background Oral submucous fibrosis (OSMF) is a chronic, progressive, and potentially malignant oral disorder that causes scarring of the oral cavity, pharynx, and...
Background Oral submucous fibrosis (OSMF) is a chronic, progressive, and potentially malignant oral disorder that causes scarring of the oral cavity, pharynx, and upper oesophagus. It is most common in Southeast Asia, but it is also found in other parts of the world. Oral potentially malignant disorders (OPMDs) are a group of oral lesions that have an increased risk of developing into oral cancer. The study aimed to evaluate the prevalence of OSMF associated with other OPMDs. The presence of multiple OPMDs existing in one patient is a significant finding, as it is associated with an elevated risk of developing malignancy. The risk of malignant transformation increases with the number of OPMDs present in a patient; patients with two OPMDs have a three to four times higher risk of developing malignancy than those with a single OPMD. Patients with three or more OPMDs have a 7-10 times higher risk and the risk of malignant transformation depends on the type of OPMD. Materials and methods The study was conducted in the Department of Oral Medicine and Radiology, Saveetha Dental College and Hospitals, Chennai, India, to investigate the prevalence of OSMF with other OPMDs. The study team retrieved 630 case records of patients with OSMF from the electronic database between January 2018 and March 2023. All of the patients in the study had OSMF, as well as other OPMDs such as leukoplakia, candidiasis, actinic cheilitis, dyskeratosis congenita, erythroplakia, lichen planus, sideropenic dysphagia (Plummer-Vinson syndrome), and discoid lupus erythematosus. Both clinical and histopathological examinations confirmed these diagnoses. Oral mucosal lesions without coexisting OSMF were excluded. The study was done on the basis of age group, habits, type of habits, associated coexisting lesions, and systemic condition. Results The patients were clinically examined and diagnosed. Of the 630 cases, 10% had OSMF with OPMDs. The most common OPMDs associated with OSMF were leukoplakia (86%), followed by candidiasis (12%) and both leukoplakia and candidiasis (2%). Based on gender, the incidence of OSMF was higher in males compared to females with 67% and 33%, respectively. Conclusion OSMF is more likely to develop into malignancy; the widespread use of areca nut products in India has contributed to the rising incidence of OSMF. Accumulating epidemiological data can help to identify high-risk populations for prevention and control measures. Earlier oral cancer diagnosis and treatment can increase the likelihood of a favourable outcome.
PubMed: 38161840
DOI: 10.7759/cureus.49642 -
Biogerontology Apr 2024Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline... (Review)
Review
Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.
Topics: Humans; Reproducibility of Results; Telomere; Telomere Shortening; Cellular Senescence; Genomic Instability; Telomerase; Neoplasms
PubMed: 38109000
DOI: 10.1007/s10522-023-10080-9 -
Hereditas Dec 2023Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with...
BACKGROUND
Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with cancer occurrence and development stages is not clear, making a pan-cancer analysis crucial.
METHODS
We conducted a study using various bioinformatic databases such as TIMER, GEPIA, UALCAN, and KM plotter Analysis to examine the different expressions of DKC1 in multiple tissues and its correlation with pathological stages. Through KEGG analysis, GO enrichment analysis and Venn analysis, we were able to reveal DKC1-associated genes and signaling pathways. In addition, we performed several tests including the CCK, wound healing assay, cell cycle arrest assay, transwell assay and Sa-β-gal staining on DKC1-deleted MDA-231 cells.
RESULTS
Our study demonstrates that DKC1 has relatively low expression specificity in different tissues. Furthermore, we found that in ACC, KICH, KIRP and LIHC, the expression level of DKC1 is positively correlated with pathological stages. Conversely, in NHSC, KIRP, LGG, LIHC, MESO and SARC, we observed a negative influence of DKC1 expression level on the overall survival rate. We also found a significant positive correlation between DKC1 expression and Tumor Mutational Burden in 14 tumors. Additionally, we observed a significantly negative impact of DKC1 DNA methylation on gene expression at the promoter region in BRCA. We also identified numerous phosphorylation sites concentrated at the C-terminus of the DKC1 protein. Our GO analysis revealed a correlation between DKC1 and ribosomal biosynthesis pathways, and the common element UTP14A was identified. We also observed decreased rates of cell proliferation, migration and invasion abilities in DKC1-knockout MDA-MB-231 cell lines. Furthermore, DKC1-knockout induced cell cycle arrest and caused cell senescence.
CONCLUSIONS
Our findings suggest that the precise expression of DKC1 is closely associated with the occurrence and developmental stages of cancer in multiple tissues. Depletion of DKC1 can inhibit the abilities of cancer cells to proliferate, migrate, and invade by arresting the cell cycle and inducing cell senescence. Therefore, DKC1 may be a valuable prognostic biomarker for the diagnosis and treatment of cancer in various tissues.
Topics: Humans; Prognosis; Cell Cycle Proteins; Dyskeratosis Congenita; Neoplasms; Biomarkers; Nuclear Proteins
PubMed: 38082360
DOI: 10.1186/s41065-023-00302-y -
BioRxiv : the Preprint Server For... Dec 2023Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and...
Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and elongation with unprecedented resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.
PubMed: 38077053
DOI: 10.1101/2023.11.29.569263 -
Hematology. American Society of... Dec 2023Hematopoietic cell transplantation (HCT) can cure blood dyscrasias and reduce the risk of hematologic cancers in patients with inherited bone marrow failure syndromes...
Hematopoietic cell transplantation (HCT) can cure blood dyscrasias and reduce the risk of hematologic cancers in patients with inherited bone marrow failure syndromes (IBMFS). However, because of its high mortality rate, HCT is generally reserved until patients with IBMFS manifest life-threatening cytopenias or myeloid malignancy, at which point outcomes are poor. Screening tests that accurately predict transformation and enable timely intervention are lacking. These unknowns and risks limit the use of HCT in patients with IBMFS, sometimes until significant disease-related sequelae have occurred. A major goal for IBMFS is to reduce cellular therapy-related complications to the point that earlier intervention can be considered before significant transfusion exposure, occurrence of comorbidities, or malignant transformation. In recent decades, disease-specific allogeneic HCT trials have yielded significant improvements in outcomes in IBMFS conditions, including Fanconi anemia and dyskeratosis congenita. This is in large part due to marked reductions in conditioning intensity to address the increased sensitivity of these patients to cytotoxic chemotherapy and radiation. The success of these approaches may also indicate an ability to leverage intrinsic fitness defects of hematopoietic stem and progenitor cells across IBMFS disorders. Now with advances in tracking somatic genetic evolution in hematopoiesis and tailored minimal intensity conditioning regimens, this question arises: is it time for preventative HCT for IBMFS?
Topics: Humans; Anemia, Aplastic; Bone Marrow Diseases; Congenital Bone Marrow Failure Syndromes; Hemoglobinuria, Paroxysmal; Bone Marrow Failure Disorders; Pancytopenia; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning
PubMed: 38066900
DOI: 10.1182/hematology.2023000470 -
Hematology. American Society of... Dec 2023Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic...
Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic comorbidities, disease defining congenital anomalies, and a susceptibility to myelodysplastic syndrome, acute myeloid leukemia, and in some instances solid tumors. The most common IBMFS include Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and telomere biology disorders/ dyskeratosis congenita. Allogeneic hematopoietic stem cell transplant (HCT) is a well-established curative treatment to correct the hematological manifestations but does not halt or reverse the nonhematological complications and may hasten them. With advances in HCT and in our ability to care for patients with IBMFS, an increasing number of survivors are making it imperative to not only diagnose but also treat late effects from the pre-, peri-, and post-HCT course and complications relating to the natural history of the syndrome. As the field of HCT evolves to allow for the incorporation of alternate graft sources, for expansion of donor options to include unrelated and mismatched donors, and for use of reduced-intensity conditioning or reduced toxicity myeloablative regimens, we have yet to determine if these advances modify the disease-specific course. While long-term outcomes of these patients are often included under one umbrella, this article seeks to address disease-specific post-HCT outcomes within IBMFS.
Topics: Humans; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow; Congenital Bone Marrow Failure Syndromes; Hemoglobinuria, Paroxysmal; Hematopoietic Stem Cell Transplantation; Disease Progression
PubMed: 38066882
DOI: 10.1182/hematology.2023000471 -
British Journal of Haematology Jan 2024Neutrophils are the shortest-lived blood cells, which requires a prodigious degree of proliferation and differentiation to sustain physiologically sufficient numbers and... (Review)
Review
Neutrophils are the shortest-lived blood cells, which requires a prodigious degree of proliferation and differentiation to sustain physiologically sufficient numbers and be poised to respond quickly to infectious emergencies. More than 10 neutrophils are produced every minute in an adult bone marrow-a process that is tightly regulated by a small group of cytokines and chemical mediators and dependent on nutrients and energy. Like granulocyte colony-stimulating factor, the primary growth factor for granulopoiesis, they stimulate signalling pathways, some affecting metabolism. Nutrient or energy deficiency stresses the survival, proliferation, and differentiation of neutrophils and their precursors. Thus, it is not surprising that monogenic disorders related to metabolism exist that result in neutropenia. Among these are pathogenic mutations in HAX1, G6PC3, SLC37A4, TAFAZZIN, SBDS, EFL1 and the mitochondrial disorders. These mutations perturb carbohydrate, lipid and/or protein metabolism. We hypothesize that metabolic disturbances may drive the pathogenesis of a subset of inherited neutropenias just as defects in DNA damage response do in Fanconi anaemia, telomere maintenance in dyskeratosis congenita and ribosome formation in Diamond-Blackfan anaemia. Greater understanding of metabolic pathways in granulopoiesis will identify points of vulnerability in production and may point to new strategies for the treatment of neutropenias.
Topics: Adult; Humans; Bone Marrow Diseases; Fanconi Anemia; Bone Marrow; Bone Marrow Failure Disorders; Neutropenia; Adaptor Proteins, Signal Transducing; Monosaccharide Transport Proteins; Antiporters
PubMed: 38049194
DOI: 10.1111/bjh.19192 -
Current Research in Translational... 2023Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired,...
Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.
Topics: Humans; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Chromosome Aberrations; Cytogenetic Analysis; Intracellular Signaling Peptides and Proteins
PubMed: 38016422
DOI: 10.1016/j.retram.2023.103423 -
La Clinica Terapeutica 2023Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death. (Review)
Review
BACKGROUND
Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death.
METHODS
During the progress of this review, we have implemented a targeted research approach, diligently choosing the most relevant and exemplary articles within the subject matter. Our method entailed a systematic exploration of the scientific literature to ensure a compre-hensive and accurate compilation of the available sources.
RESULTS
Among genodermatoses, X-linked ones are of particular importance and should always be considered when pediatric males are affected. Regardless of other syndromic forms without prevalence of skin symptoms, X-linked genodermatoses can be classified in three main groups: keratinization defects, pigmentation defects, and inflammatory skin diseases. Typical examples are dyskeratosis congenita, keratosis follicularis spinulosa decalvans, hypohidrotic ectodermal dysplasia, chondrodysplasia punctata, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, chronic granulomatous disease, CHILD syndrome and ichthyosis. In this field, genetic diagnosis of the specific disease is important, also considering that numerous clinical trials of orphan drugs and genetic therapies are being proposed for these rare genetic diseases.
CONCLUSIONS
Thus, this chapter starts from clinical to molecular testing and ends with a review of all clinical trials on orphan drugs and gene therapy for genodermatoses.
Topics: Male; Humans; Child; Ectodermal Dysplasia 1, Anhidrotic; Ichthyosis; Skin Diseases, Genetic; Genetic Diseases, X-Linked; Skin Neoplasms
PubMed: 37994770
DOI: 10.7417/CT.2023.2493