Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure

Vulliamy, Tom; Walne, Amanda J.; Baskaradas, Aroon; Mason, Philip J.; Marrone, Anna; Dokal, Inderjeet

doi:10.1016/j.bcmd.2004.12.008

Cited by 179 publications

(146 citation statements)

References 33 publications

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“…The role of abnormal telomere biology in these conditions has been covered eloquently in a review by Savage and Alter (2008). Dyskeratosis congenita (DC) and acquired aplastic anaemia have been shown to have shortened TL that is attributed to mutations in telomere associated genes such as DKC1, TERC, TERT and TINF2 in DC and TERC, TERT and TERF1 in acquired aplastic anaemia (Vulliamy et al, 2002(Vulliamy et al, , 2004(Vulliamy et al, , 2005Yamaguchi et al, 2003Yamaguchi et al, , 2005Walne et al, 2008). Other inherited bone marrow failure syndromes, such as Fanconi anaemia and Shwachman-Diamond syndrome, have also manifest shortened TL and an increased risk of both MDS and AML (Savage & Alter, 2008;Alter et al, 2009).…”

Section: Bone Marrow Failure Syndromes and Myelodysplasiamentioning

confidence: 99%

Telomere dysfunction and its role in haematological cancer

Jones¹,

Pepper²,

Baird

2012

Br J Haematol

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SummaryObservations in human tumours, as well as mouse models, have indicated that telomere dysfunction may be a key event driving genomic instability and disease progression in many solid tumour types. In this scenario, telomere shortening ultimately results in telomere dysfunction, fusion and genomic instability, creating the large-scale rearrangements that are characteristic of these tumours. It is now becoming apparent that this paradigm may also apply to haematological malignancies; indeed these conditions have provided some of the most convincing evidence of telomere dysfunction in any malignancy. Telomere length has been shown in several malignancies to provide clinically useful prognostic information, implicating telomere dysfunction in disease progression. In these malignancies extreme telomere shortening, telomere dysfunction and fusion have all been documented and correlate with the emergence of increased genomic complexity. Telomeres may therefore represent both a clinically useful prognostic tool and a potential target for therapeutic intervention.

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Section: Bone Marrow Failure Syndromes and Myelodysplasiamentioning

confidence: 99%

Telomere dysfunction and its role in haematological cancer

Jones¹,

Pepper²,

Baird

2012

Br J Haematol

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“…Subsequently mutations were found in TERC in families with autosomal dominant inheritance (Vulliamy et al 2004). TERT mutations have been described in patients with DC and in patients initially classified as having acquired AA (Savage et al 2006b;Vulliamy et al 2005;Yamaguchi et al 2005). Recessive mutations in NOP10 were recently discovered in one out of 16 consanguineous families with DC ).…”

Section: Disorders With Mutations In Telomere Biology Genes Dyskeratomentioning

confidence: 99%

The role of telomere biology in bone marrow failure and other disorders

Savage

Alter

2008

Mechanisms of Ageing and Development

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Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1 st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis.The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients are categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.

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“…Heterozygous mutations in hTR, which reduce its accumulation and perturb its structure, lead to an autosomal dominant form of DC through haploinsufficiency of the RNA subunit (5,14,45). Similarly, haploinsufficiency of TERT has been implicated in DC and in aplastic anemia (1,47,51). Limiting abundance of telomerase subunits may help to facilitate the fine balance of telomerase repression and activation associated with differentiated cells and their stem cell progenitors (15).…”

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confidence: 99%

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

Kannan

Nelson

Shippen

2008

Molecular and Cellular Biology

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Dyskerin binds the H/ACA box of human telomerase RNA and is a core telomerase subunit required for RNP biogenesis and enzyme function in vivo. Missense mutations in dyskerin result in dyskeratosis congenita, a complex syndrome characterized by bone marrow failure, telomerase enzyme deficiency, and progressive telomere shortening. Here we demonstrate that dyskerin also contributes to telomere maintenance in Arabidopsis thaliana. We report that both AtNAP57, the Arabidopsis dyskerin homolog, and AtTERT, the telomerase catalytic subunit, accumulate in the plant nucleolus, and AtNAP57 associates with active telomerase RNP particles in an RNA-dependent manner. Furthermore, AtNAP57 interacts in vitro with AtPOT1a, a novel component of Arabidopsis telomerase. Although a null mutation in AtNAP57 is lethal, AtNAP57, like AtTERT, is not haploinsufficient for telomere maintenance in Arabidopsis. However, introduction of an AtNAP57 allele containing a T66A mutation decreased telomerase activity in vitro, disrupted telomere length regulation on individual chromosome ends in vivo, and established a new, shorter telomere length set point. These results imply that T66A NAP57 behaves as a dominant-negative inhibitor of telomerase. We conclude that dyskerin is a conserved component of the telomerase RNP complex in higher eukaryotes that is required for maximal enzyme activity in vivo.

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Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure

Cited by 179 publications

References 33 publications

Telomere dysfunction and its role in haematological cancer

Telomere dysfunction and its role in haematological cancer

The role of telomere biology in bone marrow failure and other disorders

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

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