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Journal of Blood Medicine 2014Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome characterized by the classic triad of abnormal skin pigmentation, nail dystrophy, and oral... (Review)
Review
Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome characterized by the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. However, patients usually develop BMF and are predisposed to cancer, with increased risk for squamous cell carcinoma and hematolymphoid neoplasms. DC is a disease of defective telomere maintenance and is heterogeneous at the genetic level. It can be inherited in X-linked, autosomal dominant, or autosomal recessive patterns. Mutations in at least ten telomere- and telomerase-associated genes have been described in DC. There are no targeted therapies for DC and patients usually die of BMF due to a deficient renewing capability of hematopoietic stem cells. Allogeneic hematopoietic stem cell transplantation is the only curative treatment for BMF.
PubMed: 25170286
DOI: 10.2147/JBM.S47437 -
FEBS Letters Sep 2010Dyskeratosis congenita (DC) was originally defined as a rare inherited bone marrow failure (BMF) syndrome associated with distinct mucocutaneous features. Today DC is...
Dyskeratosis congenita (DC) was originally defined as a rare inherited bone marrow failure (BMF) syndrome associated with distinct mucocutaneous features. Today DC is defined by its pathogenetic mechanism and mutations in components of the telomere maintenance machinery resulting in excessively short telomeres in highly proliferating tissues. With this new definition the disease spectrum has broadened and ranges from intrauterine growth retardation, cerebellar hypoplasia, and death in early childhood to asymptomatic mutation carriers whose descendants are predisposed to malignancy, BMF, or pulmonary disease. The degree of telomere dysfunction is the major determinant of disease onset and manifestations.
Topics: Adult; Aged; Aging; Bone Marrow; Cell Division; Dyskeratosis Congenita; Genetic Diseases, Inborn; Humans; Infant, Newborn; Middle Aged; Mutation; Neoplasms; Shelterin Complex; Telomerase; Telomere; Telomere-Binding Proteins
PubMed: 20493861
DOI: 10.1016/j.febslet.2010.05.019 -
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 -
Hematology/oncology Clinics of North... Apr 2009Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized clinically by the triad of abnormal nails, reticular skin pigmentation, and oral...
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized clinically by the triad of abnormal nails, reticular skin pigmentation, and oral leukoplakia, and is associated with high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. Patients have very short germline telomeres, and approximately half have mutations in one of six genes encoding proteins that maintain telomere function. Accurate diagnosis of DC is critical to ensure proper clinical management, because patients who have DC and bone marrow failure do not respond to immunosuppressive therapy and may have increased morbidity and mortality associated with hematopoietic stem cell transplantation.
Topics: Bone Marrow Diseases; Dyskeratosis Congenita; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Telomere
PubMed: 19327580
DOI: 10.1016/j.hoc.2009.01.003 -
Advances in Experimental Medicine and... 2010Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome characterized by reticulated hyperpigmentation, dystrophic nails and oral leukoplakia. Another... (Review)
Review
Dyskeratosis congenita (DC) is an inheritable bone marrow failure syndrome characterized by reticulated hyperpigmentation, dystrophic nails and oral leukoplakia. Another name for the condition is Zinsser-Cole-Engman syndrome. Hematologic manifestations usually do not appear in childhood but later in early adulthood. Patients are also prone to carcinomas, particularly of the head and neck. The disease has X-linked or autosomal dominant/recessive inheritance. Early childhood variants (Hoyeraal-Hreidarsson syndrome) are associated with immunological abnormalities in the form of low T- and B-cell numbers. Four genes, namely DKC1 (codes for dyskerin), TERC and TERT (code for telomerase) and NOP10, have been implicated in the pathogenesis; the short telomeres provide a marker for genetic linkage studies. Androgens, with or without granulocyte colony stimulating factor, have been tried in the treatment of the conditions with variable results. Stem cell transplantation from matched sibling donor is currently the treatment of choice. It requires modified nonmyeloablative conditioning protocols, since the patients with DC are prone to pulmonary and hepatic complications.
Topics: Adult; Androgens; B-Lymphocytes; Bone Marrow Diseases; Cell Cycle Proteins; Child; Child, Preschool; Dyskeratosis Congenita; Granulocyte Colony-Stimulating Factor; Humans; Lymphocyte Count; Nuclear Proteins; RNA; Ribonucleoproteins, Small Nucleolar; T-Lymphocytes; Telomerase; Telomere
PubMed: 20687509
DOI: 10.1007/978-1-4419-6448-9_20 -
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 -
Hematology/oncology Clinics of North... Aug 2018Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to... (Review)
Review
Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increased awareness and availability of diagnostic tests in recent years. This article summarizes the pathophysiology, evaluation, and management of hematopoietic failure in patients with DC and other TBDs.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Child; Child, Preschool; Dyskeratosis Congenita; Genetic Predisposition to Disease; Hemoglobinuria, Paroxysmal; Humans; Mutation; Neoplasms; Telomere; Telomere Homeostasis
PubMed: 30047419
DOI: 10.1016/j.hoc.2018.04.003 -
Indian Dermatology Online Journal 2022
PubMed: 36386733
DOI: 10.4103/idoj.idoj_23_22 -
Frontiers in Oncology 2022Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their... (Review)
Review
Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.
PubMed: 36091172
DOI: 10.3389/fonc.2022.949435 -
American Journal of Human Genetics Aug 2022Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail...
Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.
Topics: Dyskeratosis Congenita; Germ Cells; Heterozygote; Humans; Nucleotides; Thymidylate Synthase
PubMed: 35931051
DOI: 10.1016/j.ajhg.2022.06.014