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BMJ Case Reports May 2021Dyskeratosis congenita is a rare disease caused by telomerase dysfunction classically characterised by the triad: skin pigmentation, nail dystrophy and mucosal... (Review)
Review
Dyskeratosis congenita is a rare disease caused by telomerase dysfunction classically characterised by the triad: skin pigmentation, nail dystrophy and mucosal leukoplakia. Few cases are described in literature regarding patients with head and neck squamous cell carcinoma affected by dyskeratosis congenita, and the therapeutic decisions are not yet well defined. A review of the literature of the last 20 years (2001-2021) was performed, and it was analysed the case of a 38-year-old male patient affected by dyskeratosis congenita diagnosed with a squamous cell carcinoma of the inferior alveolar ridge, treated with surgery. The absence of complications and the good postoperative recovery of the patient comfort in saying that resection and reconstructive surgery can be safely performed. The occurrence of disseminated disease 6 months after the treatment warns about the extreme aggressiveness of the pathology, its often systemic nature and the necessity of a multidisciplinary approach as well as further studies.
Topics: Adult; Alveolar Process; Carcinoma, Squamous Cell; Dyskeratosis Congenita; Head and Neck Neoplasms; Humans; Leukoplakia; Male
PubMed: 33975847
DOI: 10.1136/bcr-2021-242459 -
The Journal of Cell Biology Apr 2017Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of... (Review)
Review
Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models.
Topics: Aging; Animals; Cell Transformation, Neoplastic; Chromosomal Instability; Dyskeratosis Congenita; Fetal Growth Retardation; Humans; Intellectual Disability; Microcephaly; Molecular Targeted Therapy; Mutation; Neoplasms; Telomerase; Telomere; Telomere Homeostasis; Telomere Shortening
PubMed: 28254828
DOI: 10.1083/jcb.201610111 -
Frontiers in Genetics 2023
PubMed: 37124624
DOI: 10.3389/fgene.2023.1194788 -
Biomolecules Aug 2023Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital... (Review)
Review
Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond-Blackfan anemia), ribosome assembly (Shwachman-Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). The pathogenetic mechanisms of IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest and apoptosis of hematopoietic stem, progenitor, and precursor cells. Here, we review the IBMFSs and propose a role for pro-inflammatory cytokines, such as TGF-β, IL-1β, and IFN-α, in mediating the cytopenias. We suggest a pathogenic role for cytokines in the transformation to myeloid neoplasia and hypothesize a role for anti-inflammatory therapies.
Topics: Humans; Congenital Bone Marrow Failure Syndromes; Cytokines; Shwachman-Diamond Syndrome; Dyskeratosis Congenita; Interferon-alpha; Intracellular Signaling Peptides and Proteins
PubMed: 37627314
DOI: 10.3390/biom13081249 -
Haematologica Aug 2007
Topics: Anticipation, Genetic; Cell Cycle Proteins; Dyskeratosis Congenita; Female; Genes, Dominant; Genetic Heterogeneity; Humans; Male; Mutation; Nuclear Proteins; Phenotype; RNA; Telomerase; Telomere
PubMed: 17650438
DOI: 10.3324/haematol.11221 -
RNA Biology 2014Box H/ACA ribonucleoproteins (RNPs), each consisting of one unique guide RNA and 4 common core proteins, constitute a family of complex enzymes that catalyze, in an... (Review)
Review
Box H/ACA ribonucleoproteins (RNPs), each consisting of one unique guide RNA and 4 common core proteins, constitute a family of complex enzymes that catalyze, in an RNA-guided manner, the isomerization of uridines to pseudouridines (Ψs) in RNAs, a reaction known as pseudouridylation. Over the years, box H/ACA RNPs have been extensively studied revealing many important aspects of these RNA modifying machines. In this review, we focus on the composition, structure, and biogenesis of H/ACA RNPs. We explain the mechanism of how this enzyme family recognizes and specifies its target uridine in a substrate RNA. We discuss the substrates of box H/ACA RNPs, focusing on rRNA (rRNA) and spliceosomal small nuclear RNA (snRNA). We describe the modification product Ψ and its contribution to RNA function. Finally, we consider possible mechanisms of the bone marrow failure syndrome dyskeratosis congenita and of prostate and other cancers linked to mutations in H/ACA RNPs.
Topics: Dyskeratosis Congenita; Humans; Isomerism; Male; Mutation; Nucleic Acid Conformation; Prostatic Neoplasms; Pseudouridine; RNA Processing, Post-Transcriptional; RNA, Ribosomal; RNA, Small Nuclear; RNA, Transfer, Amino Acid-Specific; Ribonucleoproteins, Small Nuclear; Uridine; RNA, Guide, CRISPR-Cas Systems
PubMed: 25590339
DOI: 10.4161/15476286.2014.972855 -
Clinical Medicine Insights. Blood... 2014Ribosomopathies are diseases caused by alterations in the structure or function of ribosomal components. Progress in our understanding of the role of the ribosome in... (Review)
Review
Ribosomopathies are diseases caused by alterations in the structure or function of ribosomal components. Progress in our understanding of the role of the ribosome in translational and transcriptional regulation has clarified the mechanisms of the ribosomopathies and the relationship between ribosomal dysfunction and other diseases, especially cancer. This review aims to discuss these topics with updated information.
PubMed: 25512719
DOI: 10.4137/CMBD.S16952 -
The Journal of Clinical Investigation May 2016Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A... (Review)
Review
Mammalian chromosomes terminate in stretches of repetitive telomeric DNA that act as buffers to avoid loss of essential genetic information during end-replication. A multiprotein complex known as shelterin prevents recognition of telomeric sequences as sites of DNA damage. Telomere erosion contributes to human diseases ranging from BM failure to premature aging syndromes and cancer. The role of shelterin telomere protection is less understood. Mutations in genes encoding the shelterin proteins TRF1-interacting nuclear factor 2 (TIN2) and adrenocortical dysplasia homolog (ACD) were identified in dyskeratosis congenita, a syndrome characterized by somatic stem cell dysfunction in multiple organs leading to BM failure and other pleiotropic manifestations. Here, we introduce the biochemical features and in vivo effects of individual shelterin proteins, discuss shelterin functions in hematopoiesis, and review emerging knowledge implicating the shelterin complex in hematological disorders.
Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Chromosomes, Human; DNA Damage; Dyskeratosis Congenita; Hematopoiesis; Hemoglobinuria, Paroxysmal; Humans; Mutation; Shelterin Complex; Telomere; Telomere-Binding Proteins
PubMed: 27135879
DOI: 10.1172/JCI84547 -
Cancer Genetics Dec 2011Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and a variable series of other somatic... (Review)
Review
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and a variable series of other somatic abnormalities. The disease is heterogeneous at the genetic and clinical levels. Determination of the genetic basis of DC has established that the disease is caused by a number of genes, all of which encode products involved in telomere maintenance, either as part of telomerase or as part of the shelterin complex that caps and protects telomeres. There is overlap at the genetic and clinical levels with other, more common conditions, including aplastic anemia (AA), pulmonary fibrosis (PF), and liver cirrhosis. Although part of the spectrum of disorders known to be associated with DC, it has emerged that mutations in telomere maintenance genes can lead to the development of AA and PF in the absence of other DC features. Here we discuss the genetics of DC and its relationship to disease presentation.
Topics: Cell Cycle Proteins; Dyskeratosis Congenita; Genes, X-Linked; Humans; Models, Genetic; Molecular Chaperones; Nuclear Proteins; RNA; Ribonucleoproteins, Small Nuclear; Ribonucleoproteins, Small Nucleolar; Telomerase; Telomere-Binding Proteins
PubMed: 22285015
DOI: 10.1016/j.cancergen.2011.11.002 -
Annual Review of Genomics and Human... 2009Telomeres and telomerase were initially discovered in pursuit of questions about how the ends of chromosomes are maintained. The implications of these discoveries to... (Review)
Review
Telomeres and telomerase were initially discovered in pursuit of questions about how the ends of chromosomes are maintained. The implications of these discoveries to age-related disease have emerged in recent years with the recognition of a group of telomere-mediated syndromes. Telomere-mediated disease was initially identified in the context of dyskeratosis congenita, a rare syndrome of premature aging. More recently, mutations in telomerase components were identified in adults with idiopathic pulmonary fibrosis. These findings have revealed that the spectrum of telomere-mediated disease is broad and includes clinical presentations in both children and adults. We have previously proposed that these disorders be collectively considered as syndromes of telomere shortening. Here, the spectrum of these disorders and the unique telomere genetics that underlies them are reviewed. I also propose broader clinical criteria for defining telomere-mediated syndromes outside of dyskeratosis congenita, with the goal of facilitating their diagnosis and highlighting their pathophysiology.
Topics: Animals; Dyskeratosis Congenita; Genetic Predisposition to Disease; Humans; Pulmonary Fibrosis; Syndrome; Telomerase; Telomere
PubMed: 19405848
DOI: 10.1146/annurev-genom-082908-150046