X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions

Heiss, Nina S.; Knight, Stuart W.; Vulliamy, Tom; Klauck, Sabine M.; Wiemann, Stefan; Mason, Philip J.; Poustka, Annemarie; Dokal, Inderjeet

doi:10.1038/ng0598-32

Cited by 846 publications

(675 citation statements)

References 35 publications

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“…They speculated that deregulation of these genes and the pathway that they were part of, could be the causative abnormality in 5q-syndrome patients. This idea was supported by previous findings that genetic defects of ribosomal genes were implicated in congenital anemias including dyskeratosis congenita, 12 cartilage-hair hypoplasia, 13 DiamondBlackfan anemia 14 and Shwachman-Diamond syndrome. 15,16 The importance of RPS14 haplo-insufficency as a causative event in 5q-syndrome was then shown by Ebert et al using RNAi to selectively inhibit each of the 40 genes within the deleted region.…”

supporting

confidence: 62%

Defective ribosome biogenesis in myelodysplastic syndromes

Galili¹,

Qasim²,

Raza³

2009

Haematologica

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M alignant disorders are poorly understood at the biological level in general, and myelodysplastic syndromes (MDS), a heterogeneous clonal stem cell disorder, in particular, are further confounded by representing a group of diseases rather than a single entity with clinical and biological heterogeneity within each subtype. The basis for grouping these assorted diseases under one MDS umbrella is the clinical presentation of variable cytopenias despite a generally cellular and dysplastic marrow. Diagnosis is based on bone marrow morphology, percentage of blasts, unexplained cytopenias and cytogenetics. These components have been used to classify the disease (French-American British 1 or FAB and World Health Organization 2 or WHO classifications) and to predict prognosis (International Prognostic Scoring System 3 or IPSS). The typical patient is elderly; thus with the increase in our aging population, the incidence of MDS has now surpassed that of acute myeloid leukemia (AML). Approximately 30% of MDS patients will progress to AML, but the majority die from infection or bleeding due to an increasing profundity of the cytopenias. The paradox of MDS is that despite peripheral cytopenia, the marrow is most often hypercellular. The initial breakthrough in understanding the biological basis of this paradox came with the demonstration that, in MDS, bone marrow cells were not only rapidly proliferating, but also undergoing excessive apoptosis. [4][5][6][7] As a result, the maturing hematopoietic cells are eliminated in the marrow and do not reach the peripheral blood, accounting for the cytopenias in the presence of a cellular marrow composed of mostly apoptotic cells. Furthermore, it was demonstrated that multiple cytokines involved in mediating apoptosis and proliferation are deregulated in MDS marrows. [7][8][9] While the MDS cell itself probably contributes, recent insights suggest that it is the bone marrow microenvironment that is also responsible for potentiating disease pathology and progression through cytokine imbalance. In summary then, MDS appears to be a disease of both the seed and the soil (the cell and its microenvironment) where peripheral cytopenias appear to be the result of an increased proliferation-increased apoptosis in the clonal cells and deregulated proapoptotic and trophic cytokines in the marrow.Approximately half the patients with MDS present with recurring cytogenetic abnormalities most commonly affecting chromosomes 5, 7, 8, and 20. These have been shown to greatly affect prognosis and survival. 3 Despite the presence of these well recognized karyotypic aberrations, genetic mutations that accompany them have not been well understood and, in fact, mutation in a specific biological pathway that is common to multiple MDS subtypes has not been identified. In short, apoptosis has remained the sole unifying biological characteristic of the disease.Recently, however, a possible cohesive genetic explanation for this increased apoptosis has been taking shape. Initial hints began with the study of pat...

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supporting

confidence: 62%

Defective ribosome biogenesis in myelodysplastic syndromes

Galili¹,

Qasim²,

Raza³

2009

Haematologica

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“…52 X-linked DKC, which has a more severe phenotype compared with the autosomal dominant form of DKC, is caused by a mutation in DKC1, which encodes dyskerin. 53 One of the functions of dyskerin is to act as a nucleolar protein associated with the snoRNPs involved in rRNA modification. Dyskerin associates with a specific group of snoRNPs known as H/ACA, which function in the pseudo-uridylation of rRNAs.…”

Section: Dyskeratosis Congenitamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

683

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…19 Mutation of DKC1 leads to a diseased condition known as X-linked dyskeratosis congentita, which is characterized by abnormal pigmentation, bone marrow failure and an increased susceptibility to cancer. 38,39 Recently, Cayuela et al 40 has shown in transgenic TERT/ TERC À/À mice that the increased expression of TERT, in the absence of TERC genetic background, leads to reduced tumorigenesis, indicating that the tumor-promoting effects of TERT overexpression require the formation of TERT-TERC complexes. In this regard, we propose that rAAVhTERTC27-mediated downregulation of DKC1 may lead to abnormal processing and/or trafficking of hTERTC, which in turn result in telomere destabilization and eventually senescence and apoptosis in the glioblastoma tissues.…”

Section: Raav-htertc27 Treatment Induces Differential Expression Of Gmentioning

confidence: 99%

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

Gao

Chau

et al. 2007

Cancer Gene Ther

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Glioblastoma multiforme is the most aggressive form of human brain tumor, which has no effective cure. Previously, we have demonstrated that overexpression of the C-terminal fragment of the human telomerase reverse transcriptase (hTERTC27) inhibits the growth and tumorigenicity of human cervical cancer HeLa cells. In this study, the therapeutic effect and molecular mechanisms of hTERTC27-mediated cancer gene therapy were further explored in vivo in established human glioblastoma xenografts in nude mice. We showed that intratumoral injection of adeno-associated virus carrying hTERTC27 (rAAV-hTERTC27) is highly effective in reducing the growth of the subcutaneously transplanted glioblastoma tumors. Histological analyses showed that rAAV-hTERTC27 treatment leads to profound necrosis, apoptosis, infiltration of polymorphonuclear neutrophils and reduced microvessel density in the tumor samples. To study the molecular mechanism of rAAV-hTERTC27-mediated antitumor effects, we analyzed the global gene expression profiles of the rAAV-hTERTC27-treated tumor tissues and cell line as compared with that of the control rAAV-green fluorescent protein-treated samples by DNA microarray. Our results suggest that hTERTC27 exerts its effect through complex mechanisms, which involve genes regulating apoptosis, cell adhesion, cell cycle, immune responses, metabolism, signal transduction, transport, transcription and telomere maintenance.

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X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions

Cited by 846 publications

References 35 publications

Defective ribosome biogenesis in myelodysplastic syndromes

Defective ribosome biogenesis in myelodysplastic syndromes

Ribosomopathies: human disorders of ribosome dysfunction

A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide

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