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Danish Medical Journal Nov 2016The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the... (Review)
Review
The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation of PARP1 or the downstream metabolites may be a therapeutic strategy for treating accelerated aging disorders and potentially age-associated neurological decline seen in the normal population.
Topics: Aging, Premature; Animals; Ataxia Telangiectasia; Bloom Syndrome; Cockayne Syndrome; DNA Repair; Dyskeratosis Congenita; Fanconi Anemia; Humans; Mitochondria; Mitophagy; NAD; Neurodegenerative Diseases; Poly(ADP-ribose) Polymerases; Progeria; Rothmund-Thomson Syndrome; Sirtuin 1; Telomere Shortening; Werner Syndrome; Xeroderma Pigmentosum
PubMed: 27808039
DOI: No ID Found -
British Journal of Haematology Aug 2015Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis... (Review)
Review
Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.
Topics: Dyskeratosis Congenita; Fetal Growth Retardation; Humans; Intellectual Disability; Microcephaly; Mutation; Telomere; Telomere Homeostasis
PubMed: 25940403
DOI: 10.1111/bjh.13442 -
Blood Oct 2014Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita are inherited syndromes characterized by marrow failure, congenital anomalies, and cancer... (Review)
Review
Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita are inherited syndromes characterized by marrow failure, congenital anomalies, and cancer predisposition. Genetic and molecular studies have uncovered distinct abnormalities in ribosome biogenesis underlying each of these 3 disorders. How defects in ribosomes, the essential organelles required for protein biosynthesis in all cells, cause tissue-specific abnormalities in human disease remains a question of fundamental scientific and medical importance. Here we review the overlapping and distinct clinical features of these 3 syndromes and discuss current knowledge regarding the ribosomal pathways disrupted in each of these disorders. We also explore the increasing complexity of ribosome biology and how this informs our understanding of developmental biology and human disease.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Humans; Models, Biological; Protein Biosynthesis; Ribosomes
PubMed: 25237201
DOI: 10.1182/blood-2014-04-526301 -
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 Journals of Gerontology. Series A,... May 2023The underlying mechanisms of plasma metabolite signatures of human aging and age-related diseases are not clear but telomere attrition and dysfunction are central to...
The underlying mechanisms of plasma metabolite signatures of human aging and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence-associated metabolites in fibroblast-conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo, leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle (TCA) metabolites, lactate, and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species. Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data have similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human aging in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.
Topics: Humans; Animals; Mice; Dyskeratosis Congenita; Telomerase; Diabetes Mellitus, Type 2; Telomere; Mutation; Citrates; Lactates; Nuclear Proteins; Cell Cycle Proteins
PubMed: 36651908
DOI: 10.1093/gerona/glad018 -
Medical Hypotheses Jun 2022Dyskeratosis Congenita (DC) is a rare and heterogeneous disease. This disorder is resulted from a defect in the telomere maintenance in stem cells. Telomerase RNA...
Dyskeratosis Congenita (DC) is a rare and heterogeneous disease. This disorder is resulted from a defect in the telomere maintenance in stem cells. Telomerase RNA component, shelterin complex, and telomerase reverse transcriptase are mutated in this disease. Many studies have previously confirmed shorter leukocyte telomere length in DC. On the other hand, the association between telomere length and Coronavirus disease 2019 (COVID-19) indicated that people with a short telomere background mostly show more severe symptoms related to COVID-19, and the mortality rate among them increases as well. Because patients with DC have an abnormally short telomere length, in the current study, we hypothesized that they are at higher risk of developing symptomatic COVID-19 that requires further clinical care.
PubMed: 35464998
DOI: 10.1016/j.mehy.2022.110843 -
Life Science Alliance Jan 2022Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in...
Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mutation in TPP1 (K170∆) that specifically compromises telomerase recruitment to telomeres is a valuable tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mouse knocked in for the equivalent of the TPP1 K170∆ mutation (TPP1 K82∆) and investigated both its hematopoietic and germline compartments in unprecedented detail. TPP1 K82∆ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82∆ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of dysfunctional seminiferous tubules, and a decrease in germ cells. Intriguingly, both TPP1 K82∆ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to infertility at steady-state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice.
Topics: Amino Acid Sequence; Animals; CRISPR-Cas Systems; Dyskeratosis Congenita; Fertility; Gene Editing; Germ Cells; Hematopoiesis; Homozygote; Humans; Lymphopoiesis; Male; Mice; Mice, Knockout; Models, Molecular; Mutation; Organ Specificity; Sperm Count; Structure-Activity Relationship; Telomere-Binding Proteins
PubMed: 34645668
DOI: 10.26508/lsa.202101208 -
Blood Oct 2014Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and... (Review)
Review
Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and acquired disease is poorly delineated, as lesions in some genetic pathways cause stereotypical childhood syndromes and also act as risk factors for clinical manifestations in adult life. Telomere diseases are a prominent example of this relationship. Accelerated telomere attrition is the result of mutations in telomere repair genes and genes encoding components of the shelterin complex and related proteins. Genotype-phenotype correlations show genes responsible for X-linked (DKC1) and severe recessive childhood dyskeratosis congenita, typically with associated mucocutaneous features, and others (TERC and TERT) for more subtle presentation as telomeropathy in adults, in which multiorgan failure may be prominent. Telomerase mutations also are etiologic in familial pulmonary fibrosis and cryptic liver disease. Detection of a telomere disease requires awareness in the clinic, appropriate laboratory testing of telomere content, and genetic sequencing. In treatment decisions, genetic screening of related donors for hematopoietic stem cell transplantation is critical, and androgen therapy may be helpful. Telomeres shorten normally with aging, as well as under environmental circumstances, with regenerative stress and oxidative damage. Telomere biology is complexly related to oncogenesis: telomere attrition is protective by enforcing senescence or apoptosis in cells with a long mitotic history, but telomere loss also can destabilize the genome by chromosome rearrangement and aneuploidy.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Genetic Association Studies; Humans; Neoplasms; Telomerase; Telomere
PubMed: 25237198
DOI: 10.1182/blood-2014-05-526285 -
Cellular and Molecular Gastroenterology... 2023Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from...
BACKGROUND & AIMS
Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from premature telomere dysfunction experience multiorgan failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. However, the mechanism responsible for telomere dysfunction-induced liver disease remains unclear.
METHODS
We used isogenic human induced pluripotent stem cells (iPSCs) harboring a causal DC mutation in DKC1 or a CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-corrected control allele to model DC liver pathologies. We differentiated these iPSCs into hepatocytes (HEPs) or hepatic stellate cells (HSCs) followed by generation of genotype-admixed hepatostellate organoids. Single-cell transcriptomics were applied to hepatostellate organoids to understand cell type-specific genotype-phenotype relationships.
RESULTS
Directed differentiation of iPSCs into HEPs and stellate cells and subsequent hepatostellate organoid formation revealed a dominant phenotype in the parenchyma, with DC HEPs becoming hyperplastic and also eliciting a pathogenic hyperplastic, proinflammatory response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes in DKC1-mutant HEPs and hepatostellate organoids could be rescued via suppression of serine/threonine kinase AKT (protein kinase B) activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation.
CONCLUSIONS
Isogenic iPSC-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.
Topics: Humans; Induced Pluripotent Stem Cells; Hyperplasia; Liver; Cell Differentiation; Organoids; Nuclear Proteins; Cell Cycle Proteins
PubMed: 37302654
DOI: 10.1016/j.jcmgh.2023.06.003 -
Blood Oct 2020Inherited bone marrow failure syndromes (IBMFSs) are characterized by ineffective hematopoiesis and increased risk for developing myeloid malignancy. The... (Review)
Review
Inherited bone marrow failure syndromes (IBMFSs) are characterized by ineffective hematopoiesis and increased risk for developing myeloid malignancy. The pathophysiologies of different IBMFSs are variable and can relate to defects in diverse biological processes, including DNA damage repair (Fanconi anemia), telomere maintenance (dyskeratosis congenita), and ribosome biogenesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome). Somatic mutations leading to clonal hematopoiesis have been described in IBMFSs, but the distinct mechanisms by which mutations drive clonal advantage in each disease and their associations with leukemia risk are not well understood. Clinical observations and laboratory models of IBMFSs suggest that the germline deficiencies establish a qualitatively impaired functional state at baseline. In this context, somatic alterations can promote clonal hematopoiesis by improving the competitive fitness of specific hematopoietic stem cell clones. Some somatic alterations relieve baseline fitness constraints by normalizing the underlying germline deficit through direct reversion or indirect compensation, whereas others do so by subverting senescence or tumor-suppressor pathways. Clones with normalizing somatic mutations may have limited transformation potential that is due to retention of functionally intact fitness-sensing and tumor-suppressor pathways, whereas those with mutations that impair cellular elimination may have increased risk for malignant transformation that is due to subversion of tumor-suppressor pathways. Because clonal hematopoiesis is not deterministic of malignant transformation, rational surveillance strategies will depend on the ability to prospectively identify specific clones with increased leukemic potential. We describe a framework by which an understanding of the processes that promote clonal hematopoiesis in IBMFSs may inform clinical surveillance strategies.
Topics: Animals; Biomarkers; Clonal Evolution; Clonal Hematopoiesis; Congenital Bone Marrow Failure Syndromes; DNA Damage; Diagnosis, Differential; Disease Susceptibility; Genetic Predisposition to Disease; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mutation; Phenotype
PubMed: 32736377
DOI: 10.1182/blood.2019000990