X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation

Safa, Wassef F.

doi:10.1136/thorax.56.11.891

Cited by 38 publications

(34 citation statements)

References 20 publications

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“…A DKC1p.A2V Epstein-Barr virustransformed LCL was generated from the blood sample by the tissue culture core laboratory within the Department of Molecular and Human Genetics, Baylor College of Medicine. The DKCp.A2V mutation was reported previously (Knight et al 1999;Safa et al 2001). The development of TIN2p.R282fs36X and control unaffected sibling LCLs was described (Sasa et al 2011).…”

Section: Lclsmentioning

confidence: 73%

A role for heterochromatin protein 1γ at human telomeres

Canudas¹,

Houghtaling²,

Bhanot³

et al. 2011

Genes Dev.

106

122

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Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1g (HP1g), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1g localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1g and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1g in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC.

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Section: Lclsmentioning

confidence: 73%

A role for heterochromatin protein 1γ at human telomeres

Canudas¹,

Houghtaling²,

Bhanot³

et al. 2011

Genes Dev.

106

122

View full text Add to dashboard Cite

show abstract

“…Some evidence indicates that genomic instability, as caused by defects in DNA repair mechanisms, may contribute to fibrotic lung diseases, since some patients with the premature ageing disease dyskeratosis congenital develop pulmonary fibrosis [196]. Secondly, the ataxia telangiectasia gene is an important sensor of DNA damage and a subset of patients with ataxia telangiectasia develop forms of interstitial lung disease [197].…”

Section: Genomic Instabilitymentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…Evidence for a physiologically important role of telomerase in humans first emerged from analysis of the genetic syndrome dyskeratosis congenita (DKC), characterized by failure of bone morrow and other rapidly dividing cell lineages. An X-linked form of DKC was the first human disease recognized to be related to telomerase deficiency and is caused by the mutation of the gene encoding dyskerin, a protein component of the telomerase complex (4)(5)(6). Subsequently, mutations of TERT and TERC have been shown to result in DKC and to be risk factors for a range of other human telomeric syndromes, including aplastic anemia, idiopathic pulmonary fibrosis, and acute myeloid leukemia (7).…”

mentioning

confidence: 99%

Telomere length is inherited with resetting of the telomere set-point

Chiang

Calado

Hathcock

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert +/− heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert +/− mice were intercrossed to produce genotypically wild-type Tert +/+ mice, for which telomere length was characterized. Strikingly, telomere length in these Tert +/+ mice was not longer than that of their Tert +/− parents. Moreover, when successive crosses were carried out among these short-telomere Tert +/+ offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.T elomerase is an RNA-dependent DNA polymerase that consists of two essential components, a template RNA (TERC) and a catalytic reverse transcriptase (TERT). The telomerase holoenzyme adds telomeric DNA repeats at the termini of eukaryotic chromosomes, thus maintaining telomere length and function despite telomere attrition that normally occurs during chromosomal replication. Telomeric DNA repeats and specific associated proteins are assembled to form telomere structures that distinguish normal chromosome ends from DNA damage-induced double-strand breaks and thus subserve a critical function in maintaining chromosomal stability (1-3). The functional importance of telomere integrity and telomerase activity has been addressed in a variety of experimental model systems, notably including genetic alterations of telomerase and telomeric proteins in multiple eukaryotic species. Evidence for a physiologically important role of telomerase in humans first emerged from analysis of the genetic syndrome dyskeratosis congenita (DKC), characterized by failure of bone morrow and other rapidly dividing cell lineages. An X-linked form of DKC was the first human disease recognized to be related to telomerase deficiency and is c...

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X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation

Cited by 38 publications

References 20 publications

A role for heterochromatin protein 1γ at human telomeres

A role for heterochromatin protein 1γ at human telomeres

Hallmarks of the ageing lung

Telomere length is inherited with resetting of the telomere set-point

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