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Orphanet Journal of Rare Diseases Oct 2020Revesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature. (Review)
Review
BACKGROUND
Revesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature.
METHODS
To further characterize the typical features and natural course of the disease, we screened the English literature and summarized the clinical and epidemiological features of previously published RS cases. In addition, we herein describe the first recorded patient in central Europe.
RESULTS
The literature review included 18 children. Clinical features are summarized, indicating a low prevalence of the classical DKC triad. All patients experienced early bone marrow failure, in most cases within the second year of life (median age 1.5 years; 95% CI 1.4-1.6). Retinopathy occurred typically between 6 and 18 months of age (median age 1.1 years; 95% CI 0.7-1.5). The incidence of seizures was low and was present in an estimated 20% of patients. The onset of seizures was exclusively during early childhood. The Kaplan-Meier estimate of survival was dismal (median survival 6.5 years; 95% CI 3.6-9.4), and none of the patients survived beyond the age of 12 years. Stem cell transplantation (SCT) was performed in eight children, and after a median of 22 months from SCT four of these patients were alive at the last follow up visit.
CONCLUSION
RS is a severe variant of DKC with early bone marrow failure and retinopathy in all patients. Survival is dismal, but stem cell transplantation may be performed successfully and might improve prognosis in the future.
Topics: Bone Diseases, Metabolic; Bone Marrow; Child; Child, Preschool; Dyskeratosis Congenita; Europe; Humans; Infant; Retina
PubMed: 33097095
DOI: 10.1186/s13023-020-01553-y -
The New England Journal of Medicine Apr 2017
Topics: Blood Cell Count; Dyskeratosis Congenita; Humans; Leukoplakia; Male; Nail Diseases; Telomere
PubMed: 28402761
DOI: 10.1056/NEJMicm1613081 -
Best Practice & Research. Clinical... Jun 2019Myelodysplastic syndromes and acute myeloid leukemia are sporadic for the majority of cases affecting the elderly population. Inherited cases, however, do occur. Genetic... (Review)
Review
Myelodysplastic syndromes and acute myeloid leukemia are sporadic for the majority of cases affecting the elderly population. Inherited cases, however, do occur. Genetic predispositions to myeloid malignancies can be classified into three categories: familial cancer syndromes associated with increased risk of various malignancies including myelodysplasia and acute myeloid leukemia such as Li-Fraumeni syndrome and constitutional mismatch repair deficiency (CMMRD); germline mutations conferring a specific increased risk of myelodysplastic syndrome and acute myeloid leukemia such as mutations in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes; and finally primarily pediatric inherited bone marrow failure syndromes such as Fanconi anemia, dyskeratosis congenita, severe congenital neutropenia, Shwachman-Diamond syndrome and Diamond Blackfan anemia. The recognition of these germline syndromes is essential in the management and follow-up of patients. Herein, we review the conditions associated with hereditary myeloid leukemia with a special clinical focus on management and monitoring.
Topics: Germ-Line Mutation; Hematologic Neoplasms; Humans; Myeloproliferative Disorders; Neoplasm Proteins; Neoplastic Syndromes, Hereditary
PubMed: 31203998
DOI: 10.1016/j.beha.2019.05.001 -
Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA.Cell Sep 2014Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here,...
Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here, we develop Ψ-seq for transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with spike-ins and de novo identification of previously reported positions and discover hundreds of unique sites in human and yeast mRNAs and snoRNAs. Perturbing pseudouridine synthases (PUS) uncovers which pseudouridine synthase modifies each site and their target sequence features. mRNA pseudouridinylation depends on both site-specific and snoRNA-guided pseudouridine synthases. Upon heat shock in yeast, Pus7p-mediated pseudouridylation is induced at >200 sites, and PUS7 deletion decreases the levels of otherwise pseudouridylated mRNA, suggesting a role in enhancing transcript stability. rRNA pseudouridine stoichiometries are conserved but reduced in cells from dyskeratosis congenita patients, where the PUS DKC1 is mutated. Our work identifies an enhanced, transcriptome-wide scope for pseudouridine and methods to dissect its underlying mechanisms and function.
Topics: Animals; Candida albicans; Cell Cycle Proteins; Dyskeratosis Congenita; Gene Expression Profiling; Humans; Intramolecular Transferases; Mice; Molecular Sequence Data; Nuclear Proteins; Pseudouridine; RNA; RNA, Messenger; RNA, Ribosomal; RNA, Untranslated; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Substrate Specificity; Telomerase
PubMed: 25219674
DOI: 10.1016/j.cell.2014.08.028 -
Faculty Reviews 2022Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to... (Review)
Review
Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to interstitial lung disease and liver cirrhosis, from childhood (dyskeratosis congenita) to old age (pulmonary fibrosis). The molecular mechanisms underlying these clinically distinct disorders are pathologically excessive telomere erosion, limiting cell proliferation and differentiation, tissue regeneration, and increasing genomic instability. Recent findings also indicate that telomere shortening imbalances stem cell fate and is associated with an abnormal inflammatory response and the senescent-associated secretory phenotype. Bone marrow failure is the most common phenotype in patients with telomere diseases. Pulmonary fibrosis is a typical phenotype in older patients, and disease progression appears faster than in pulmonary fibrosis not associated with telomeropathies. Liver cirrhosis may present in isolation or in combination with other phenotypes. Diagnosis is based on clinical suspicion and may be confirmed by telomere length measurement and genetic testing. Next-generation sequencing (NGS) techniques have improved genetic testing; today, at least 16 genes have been implicated in telomeropathies. NGS also allows tracking of clonal hematopoiesis and malignant transformation. Patients with telomere diseases are at high risk of developing cancers, including myeloid neoplasms and head and neck cancer. However, treatment options are still limited. Transplant modalities (bone marrow, lung, and liver) may be definitive to the respective organ involvement but limited by donor availability, comorbidities, and impact on other affected organs. In clinical trials, androgens elongate telomeres of peripheral blood leukocytes and improve hematopoiesis. Further understanding of how telomere erosion impairs organ function and how somatic mutations evolve in the hematopoietic tissue may help develop new strategies to treat and prevent telomere diseases.
PubMed: 36311538
DOI: 10.12703/r/11-31 -
The Journal of Biological Chemistry 2021Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of... (Review)
Review
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.
Topics: Anemia, Aplastic; Dyskeratosis Congenita; Humans; Mutation; Shelterin Complex; Telomerase; Telomere; Telomere Shortening; Telomere-Binding Proteins
PubMed: 33482595
DOI: 10.1074/jbc.REV120.014017 -
International Journal of Molecular... Jul 2020Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both... (Review)
Review
Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.
Topics: Animals; Humans; Ligands; Neoplasms; Nuclear Proteins; Nucleic Acids; Nucleophosmin; Proteins
PubMed: 32664415
DOI: 10.3390/ijms21144885 -
Journal of Oral and Maxillofacial... 2017Telomeres are repetitive ribonucleoprotein complexes present at ends of chromosomes. To synthesize this manuscript, a thorough literature search was done using PubMed,... (Review)
Review
Telomeres are repetitive ribonucleoprotein complexes present at ends of chromosomes. To synthesize this manuscript, a thorough literature search was done using PubMed, MEDLINE and Cochrane review for English-language literature and data available from the period of 2005-2016 were analyzed for manuscript writing. Telomeres help in maintaining the cellular health, inbuilt cellular mechanisms, metabolism and normal cell cycle. Telomerase is a specialized enzyme that possesses catalytic subunits - reverse transcriptase, Terc and dyskerin. Mutations affecting telomere or any component of telomerase enzyme result in disorders such as dyskeratosis congenita, aplastic anemia, myelodysplastic syndromes and leukemias. Thus, it is important to understand the telomere biology so as to deal with normal physiologic processes such as apoptosis, aging and senescence and tumor development.
PubMed: 28479693
DOI: 10.4103/jomfp.JOMFP_39_16 -
Ophthalmology and Therapy Sep 2019Dyskeratosis congenita is a syndrome of bone marrow failure secondary to unstable telomeres. It is characterized by a range of mucocutaneous diseases. Due to premature...
Dyskeratosis congenita is a syndrome of bone marrow failure secondary to unstable telomeres. It is characterized by a range of mucocutaneous diseases. Due to premature telomere shortening, these patients have limbal stem cell deficiency leading to poor regeneration and maintenance of the cornea. Many of these patients will require hematopoietic stem cell transplant in their lifetime, which poses a significant risk for acute and chronic graft-versus-host disease with and without ocular manifestations. We advise against elective corneal refractive surgery in patients with dyskeratosis congenita due to the compounded and long-term risks of delayed healing secondary to limbal stem cell deficiency and ocular complications of graft-versus-host disease post-allogeneic hematopoietic stem cell transplant.
PubMed: 31313220
DOI: 10.1007/s40123-019-0200-z