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Background: Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD). Summary: Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis. Key Messages: The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood. [ABSTRACT FROM AUTHOR]

The protection of telomere protein (POT1) is a telomere‐binding protein and is an essential component of the six‐membered shelterin complex, which is associated with the telomeres. POT1 directly binds to the 3′ single‐stranded telomeric overhang and prevents the activation of DNA damage response at telomeres thus preventing the telomere–telomere fusions and genomic instability. POT1 also plays a pivotal role in maintaining telomere length by regulating telomerase‐mediated telomere elongation. Mutations in POT1 proteins result in three different telomere phenotypes, which include long, short, or aberrant telomere length. Long telomeres predispose individuals to cancer, while short or aberrant telomere phenotypes result in pro‐aging diseases referred to as telomeropathies. Here, we review the function of POT1 proteins in telomere length hemostasis and how the spectrum of mutations reported in POT1 can be segregated toward developing very distinct disease phenotypes of cancer and telomeropathies. [ABSTRACT FROM AUTHOR]

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling. [ABSTRACT FROM AUTHOR]

Les télomères sont composés d'une séquence répétée de nucléotides double brin TTAGGG et sont associés à de nombreuses protéines dont le complexe « Shelterin ». Leur rôle principal est de maintenir la stabilité du génome lors de la réplication cellulaire grâce à un mécanisme de copie de la séquence répétée par le complexe télomérase. L'ensemble des pathologies impliquant une dérégulation de la maintenance des télomères sont maintenant réunies sous le terme de téloméropathies. L'objectif de notre étude était de décrire les caractéristiques clinico-biologiques et thérapeutiques dans une cohorte de patients atteints de téloméropathie de recrutement hématologique suivis en médecine interne au centre hospitalier universitaire de Lille. Il s'agit d'une étude rétrospective, unicentrique réalisée au sein du service de médecine interne-immunologie clinique, centre de référence des maladies auto-immunes et systémique rares au CHU de Lille entre 2005 et 2020 incluant l'ensemble des patients suivis pour téloméropathie. Des cas index et des apparentés ont été inclus. Les 15 patients étudiés étaient issus de 10 familles indépendantes. Soixante pour cent étaient porteurs d'une mutation du gène TERC à l'état hétérozygote. Soixante-sept pour cent avaient une atteinte hématologique comprenant notamment une macrocytose avec anémie et/ou thrombopénie, 20 % une atteinte hépatique et 27 % une atteinte pulmonaire de type fibrosante. L'immunophénotypage lymphocytaire montrait la présence d'une population lymphocytaire T double négative avec une expression de TCR γδ pour 5 (33 %) d'entre eux. Quarante-sept pour cent des patients n'avaient reçu aucun traitement. Vingt-sept pour cent étaient sous androgène. Vingt pour cent avaient reçu de la ciclosporine et 13 % du sérum anti-lymphocytaire dans un contexte de diagnostic erroné d'une aplasie acquise. Il est important pour le médecin interniste d'être sensibilisé à la complexité des téloméropathies, diagnostic différentiel des aplasies médullaires acquises idiopathiques, pour pouvoir optimiser la prise en charge et éviter les thérapeutiques inappropriées. L'allogreffe de cellules souches hématopoïétiques est le seul traitement potentiellement curatif. Notre analyse a rapporté des particularités à l'immunophénotypage lymphocytaire non décrites à notre connaissance dont l'imputabilité physiopathologique reste à démontrer. Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated. [ABSTRACT FROM AUTHOR]

Abstract Background Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. Methods This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. Results Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. Conclusion Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.

Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Telomeropathies involve a wide variety of infrequent genetic diseases caused by mutations in the telomerase maintenance mechanism or the DNA damage response (DDR) system. They are considered a family of rare diseases that often share causes, molecular mechanisms and symptoms. Generally, these diseases are not diagnosed until the symptoms are advanced, diminishing the survival time of patients. Although several related syndromes may still be unrecognized this work describes those that are known, highlighting that because they are rare diseases, physicians should be trained in their early diagnosis. The etiology and diagnosis are discussed for each telomeropathy and the treatments when available, along with a new classification of this group of diseases. Ethical and legal issues related to this group of diseases are also considered. [ABSTRACT FROM AUTHOR]

Telomeres are located at the end of the chromosomes. They protect chromosomes from fusion and degradation. Every cell division causes a shortening of the telomeres. A special enzymatic complex called telomerase is responsible for maintaining telomere length in intensively dividing cells, such as epithelial cells and bone marrow cells. The enzymatic complex includes the TERT subunit, which has reverse transcriptase activity, and the TERC subunit, which acts as a template. Other important components of telomerase are the proteins that are responsible for structural stability. Telomerase remains active only in the dividing cells of the body. The rate of telomere shortening depends on many factors including age, sex, and comorbidities. Faster shortening of telomeres is caused by gene defects, which have an impact on telomerase action. Collectively, these are called telomeropathies. Common causes of telomeropathies are mutations in the TERT and TERC telomerase genes. Types of telemeropathies include dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anaemia, among others. Clinical manifestations and prognoses depend on the type and quantity of mutated genes. Diagnosis of telomeropathies is often problematic because they present with the same symptoms as other diseases. So far, no effective therapeutic methods have been developed for telomeropathies. A therapeutic method for patients with bone marrow failure may be the transplantation of hematopoietic stem cells. For patients with idiopathic pulmonary fibrosis, treatments include immunosuppressive therapy, lung transplantation, or palliative care. In the future, gene therapy may be an effective treatment strategy for telomeropathies. Lifestyle changes may also have a positive impact on the person. Physical activity combined with a healthy diet rich in antioxidants and unsaturated fatty acids can decrease the oxidative stress levels in cells and lead to a slower shortening of the telomeres. [ABSTRACT FROM AUTHOR]

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients.Methods: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes.Results: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening.Conclusion: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed. [ABSTRACT FROM AUTHOR]

Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.