The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Justine D Miller - One of the best experts on this subject based on the ideXlab platform.
-
telomere elongation in induced pluripotent stem cells from Dyskeratosis Congenita patients
Nature, 2010Co-Authors: Suneet Agarwal, Erin M Mcloughlin, Junjiu Huang, Inhyun Park, Justine D MillerAbstract:Patients with Dyskeratosis Congenita, a disorder of telomere maintenance, suffer degeneration of multiple tissues. Agarwal et al. use iPS (induced pluripotent stem) cell technology to study the mechanisms underlying the disease in humans, and in doing so they discover that reprogramming restores telomere elongation in Dyskeratosis Congenita cells despite genetic lesions affecting telomerase. The reprogrammed Dyskeratosis Congenita cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors. Strategies designed to increase TERC expression may therefore be therapeutically beneficial in Dyskeratosis Congenita patients. Here, iPS cell technology is used to study the mechanisms underlying Dyskeratosis Congenita in humans. Reprogramming restores telomere elongation in Dyskeratosis Congenita cells despite genetic lesions affecting telomerase. The reprogrammed cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors. Patients with Dyskeratosis Congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues1,2,3. Patient-specific induced pluripotent stem (iPS) cells4 represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)5,6,7. We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3′ deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.
Inderjeet Dokal - One of the best experts on this subject based on the ideXlab platform.
-
Mutations in the telomerase component NHP2 cause the premature ageing syndrome Dyskeratosis Congenita
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Tom Vulliamy, Anna Marrone, Amanda J. Walne, Richard Beswick, Michael Kirwan, Martin Digweed, Inderjeet DokalAbstract:Dyskeratosis Congenita is a premature aging syndrome characterized by muco-cutaneous features and a range of other abnormalities, including early greying, dental loss, osteoporosis, and malignancy. Dyskeratosis Congenita cells age prematurely and have very short telomeres. Patients have mutations in genes that encode components of the telomerase complex (dyskerin, TERC, TERT, and NOP10), important in the maintenance of telomeres. Many Dyskeratosis Congenita patients remain uncharacterized. Here, we describe the analysis of two other proteins, NHP2 and GAR1, that together with dyskerin and NOP10 are key components of telomerase and small nucleolar ribonucleoprotein (snoRNP) complexes. We have identified previously uncharacterized NHP2 mutations that can cause autosomal recessive Dyskeratosis Congenita but have not found any GAR1 mutations. Patients with NHP2 mutations, in common with patients bearing dyskerin and NOP10 mutations had short telomeres and low TERC levels. SiRNA-mediated knockdown of NHP2 in human cells led to low TERC levels, but this reduction was not observed after GAR1 knockdown. These findings suggest that, in human cells, GAR1 has a different impact on the accumulation of TERC compared with dyskerin, NOP10, and NHP2. Most of the mutations so far identified in patients with classical Dyskeratosis Congenita impact either directly or indirectly on the stability of RNAs. In keeping with this effect, patients with dyskerin, NOP10, and now NHP2 mutations have all been shown to have low levels of telomerase RNA in their peripheral blood, providing direct evidence of their role in telomere maintenance in humans.
-
Dyskeratosis Congenita: a disorder of telomerase deficiency and its relationship to other diseases
Expert Review of Dermatology, 2006Co-Authors: Anna Marrone, Inderjeet DokalAbstract:Dyskeratosis Congenita is a heterogeneous inherited bone marrow failure syndrome that is classically characterized by abnormal skin pigmentation, nail dystrophy and leukoplakia. X-linked recessive Dyskeratosis Congenita is due to mutations in DKC1, which encodes dyskerin. This protein is a key component in pseudouridylation and for telomere maintenance through the stabilization of the telomerase complex. Autosomal dominant Dyskeratosis Congenita has been found to be due to mutations in TERC and TERT that encode two key components (telomerase RNA component and reverse transcriptase) of the telomerase complex. These observations, together with the finding of shorter than expected telomeres in all Dyskeratosis Congenita patients, suggest that Dyskeratosis Congenita is primarily a disorder of telomerase deficiency. At present, it is unclear if defective pseudouridylation and/or rRNA processing plays any role in the pathophysiology of X-linked Dyskeratosis Congenita, but the clinical phenotype observed in high...
-
Dyskeratosis Congenita: telomerase, telomeres and anticipation.
Current opinion in genetics & development, 2005Co-Authors: Anna Marrone, Amanda J. Walne, Inderjeet DokalAbstract:Dyskeratosis Congenita (DC) is a rare bone marrow failure syndrome that displays marked clinical and genetic heterogeneity. The identification of Dyskeratosis Congenita gene 1 (DKC1) mutations in X-linked recessive patients initially suggested that DC is a defective pseudouridylation disorder. The subsequent identification of mutations in the telomerase RNA component (TERC) of autosomal dominant DC patients together with the discovery that both TERC and the DKC1-encoded protein, dyskerin, are closely associated in the telomerase complex have suggested that the pathophysiology of DC predominantly relates to defective telomere maintenance. Recent discoveries have shown that autosomal dominant DC exhibits disease anticipation and that this is associated with progressive telomere shortening owing to the haplo-insufficiency of TERC.
-
Peripheral neuropathy—a novel finding in Dyskeratosis Congenita
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2005Co-Authors: Ravi Knight, Inderjeet Dokal, Adnan Y. Manzur, Francesco MuntoniAbstract:We report the case of a 3.5-year-old boy who presented with truncal ataxia, microcephaly and delayed global development in infancy. Hypoplasia of cerebellum and corpus callosum and delayed myelination were found on brain MRI. Failure to thrive, sparse hairs and dystrophic nails became evident at the age of 2 years. He subsequently developed bleeding tendency, thrombocytopenia and hypocellularity on bone marrow examination leading to a diagnosis of Dyskeratosis Congenita. Impaired pain perception with slowing of nerve conduction velocities was demonstrated, suggesting a mild peripheral neuropathy. To the best of our knowledge, peripheral neuropathy has never been reported as a feature of the Congenital form of Dyskeratosis Congenita.
-
the rna component of telomerase is mutated in autosomal dominant Dyskeratosis Congenita
Nature, 2001Co-Authors: Tom Vulliamy, Monica Bessler, Philip J. Mason, Anna Marrone, Frederick D Goldman, Andrew Dearlove, Inderjeet DokalAbstract:Dyskeratosis Congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy1,2. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA4. Dyskerin is also associated with telomerase RNA (hTR)5, which contains a H/ACA consensus sequence6,7. Here we map the gene responsible for Dyskeratosis Congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3′ 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant Dyskeratosis Congenita.
John I. Harper - One of the best experts on this subject based on the ideXlab platform.
-
Dyskeratosis Congenita: delay in diagnosis and successful treatment of pancytopenia by bone marrow transplantation.
The British journal of dermatology, 1992Co-Authors: R.j. Phillips, Mary Judge, D. Webb, John I. HarperAbstract:Summary Dyskeratosis Congenita is an inherited disorder characterized by nail dystrophy, skin pigmentary changes, mucosal leukoplakia, pancytopenia and an increased incidence of malignancy. Because of a widely held view that the outcome of bone marrow transplantation in Dyskeratosis Congenita is poor, this treatment option is sometimes not considered when pancytopenia develops. We present a child currently doing well 3 years after bone marrow transplantation, and review the literature.
Suneet Agarwal - One of the best experts on this subject based on the ideXlab platform.
-
telomere elongation in induced pluripotent stem cells from Dyskeratosis Congenita patients
Nature, 2010Co-Authors: Suneet Agarwal, Erin M Mcloughlin, Junjiu Huang, Inhyun Park, Justine D MillerAbstract:Patients with Dyskeratosis Congenita, a disorder of telomere maintenance, suffer degeneration of multiple tissues. Agarwal et al. use iPS (induced pluripotent stem) cell technology to study the mechanisms underlying the disease in humans, and in doing so they discover that reprogramming restores telomere elongation in Dyskeratosis Congenita cells despite genetic lesions affecting telomerase. The reprogrammed Dyskeratosis Congenita cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors. Strategies designed to increase TERC expression may therefore be therapeutically beneficial in Dyskeratosis Congenita patients. Here, iPS cell technology is used to study the mechanisms underlying Dyskeratosis Congenita in humans. Reprogramming restores telomere elongation in Dyskeratosis Congenita cells despite genetic lesions affecting telomerase. The reprogrammed cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors. Patients with Dyskeratosis Congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues1,2,3. Patient-specific induced pluripotent stem (iPS) cells4 represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)5,6,7. We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3′ deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.
Athena M. Cherry - One of the best experts on this subject based on the ideXlab platform.
-
Telomere shortening and loss of self-renewal in Dyskeratosis Congenita induced pluripotent stem cells
Nature, 2011Co-Authors: Luis F.z. Batista, Matthew F. Pech, Franklin L. Zhong, Ha Nam Nguyen, Kathleen T. Xie, Arthur J. Zaug, Sharon M. Crary, Jinkuk Choi, Vittorio Sebastiano, Athena M. CherryAbstract:Dyskeratosis Congenita, a disease characterized by defective maintenance of blood, pulmonary and epidermal tissues, is caused by defects in genes required for telomere homeostasis. Short telomeres are thought to cause signs of the disease in mouse models by inducing senescence and cell death responses that impair tissue stem-cell function. Batista et al. generated induced pluripotent stem (iPS) cells from Dyskeratosis Congenita patients. Previously reported iPS-cell-based disease models have required iPS cells to be differentiated to a terminal cell type before cellular defects emerge. In this instance, many features of the human stem-cell disease are found in patient-derived iPS cells, providing a model that is not dependent on cell differentiation to study disease mechanisms or to identify potential therapeutics. The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease1,2,3,4,5,6. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis Congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis7,8. Short telomeres, a hallmark of Dyskeratosis Congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of Dyskeratosis Congenita9,10. Here we show that even in the undifferentiated state, iPSCs from Dyskeratosis Congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked Dyskeratosis Congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of Dyskeratosis Congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in Dyskeratosis Congenita patients. These findings in iPSCs from Dyskeratosis Congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell-culture-based system for the development of targeted therapeutics.