Original Article
Telomerase Mutations in Families with Idiopathic Pulmonary Fibrosis
N Engl J Med 2007; 356:1317-1326March 29, 2007
- Abstract
Background
Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis.
Methods
To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR.
Results
Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families.
Conclusions
Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease.
Media in This Article
Figure 1
Pedigrees of Six Probands with Telomerase Mutations.Figure 2
Telomere Length in Mutation Carriers and Their Relatives.Article Activity
- Article
Idiopathic pulmonary fibrosis has a predictable, progressive clinical course that ultimately leads to respiratory failure. Irreversible fibrosis is the hallmark of the disease, which has a characteristic radiographic appearance most often associated with the pathological lesion of usual interstitial pneumonia. Although both genetic and environmental factors have been implicated, the cause of idiopathic pulmonary fibrosis is unknown — as, indeed, its name implies. Treatment approaches that target the immune system have not proved to be successful.1 From 2 to 20% of patients with idiopathic pulmonary fibrosis have a family history of the disease; inheritance appears to be autosomal dominant with variable penetrance.1-3 Aside from one large kindred with a mutation in the gene encoding surfactant protein C in affected family members, the genetic basis of familial forms of idiopathic pulmonary fibrosis is not understood.4
Telomerase is a specialized polymerase that adds telomere repeats to the ends of chromosomes.5 It has two essential components: a catalytic component, telomerase reverse transcriptase (hTERT), and an RNA component (hTR); the latter provides the template for nucleotide addition by hTERT.6-8 The addition of telomeric repeats (a repeat comprising the six nucleotides — TTAGGG — complementary to the template in hTR) onto the ends of the chromosome partly offsets the shortening that occurs during DNA replication. Telomeres shorten with each cell division and ultimately activate a DNA damage response that leads to apoptosis or cell-cycle arrest.9-13 Telomere length thus limits the replicative capacity of tissues and has been implicated in age-related disease.9-11,14,15
Dyskeratosis congenita is a rare hereditary disorder initially described on the basis of a triad of mucocutaneous manifestations: skin hyperpigmentation, oral leukoplakia, and nail dystrophy.16 The most common cause of death in patients with dyskeratosis congenita is bone marrow failure due to aplastic anemia. Pulmonary disease is present in 20% of patients and is the second most common cause of death.16-18 The X-linked form of dyskeratosis congenita is severe and associated with mutations in the DKC1 gene.19 Autosomal dominant cases of dyskeratosis congenita are rare, can present later in adulthood, and often lack the classic skin manifestations. In some families, the hematopoietic defects develop first, implying that despite the originally given name, the dyskeratosis is not canonical.20 Heterozygous mutations in hTR and hTERT, the essential components of telomerase, underlie the genetic defect in families with dominant inheritance, indicating that half the usual dose of telomerase is inadequate for telomere maintenance, and tissues of high turnover, such as the bone marrow, are susceptible.21-24 In autosomal dominant dyskeratosis congenita, anticipation can be seen in which phenotypes present earlier and more severely in successive generations.21,24,25 This pattern implies that in these patients, it is not the telomerase mutation itself but the short telomeres that determine the severity of the disease.14,24,26
We recently identified a pedigree with autosomal dominant dyskeratosis congenita that carried a null hTERT allele but lacked the typical mucocutaneous features.24 In this kindred, pulmonary fibrosis was dominantly transmitted and was the only manifestation of disease in one mutation carrier. The clinical presentation and pattern of fibrosis in this subject were typical of the idiopathic form of the disease. Since familial idiopathic pulmonary fibrosis is also dominantly inherited, we hypothesized that telomere shortening causes this disease and that mutations in telomerase may contribute to it.
Methods
Subjects
Subjects and their families were recruited into the Vanderbilt Familial Pulmonary Fibrosis Registry on the basis of the presence of two or more cases of idiopathic pulmonary fibrosis. (We did not limit families to those in which only first-degree relatives were affected.) Subjects were excluded from the study if they had a secondary cause of pulmonary fibrosis or if they had skin manifestations suggestive of dyskeratosis congenita. Subjects were recruited from the Vanderbilt Idiopathic Pulmonary Fibrosis Clinic or were referred from other sites in North America between 1996 and 2004. The study was approved by the local institutional review boards, and written informed consent was obtained from all subjects. Diagnostic confirmation was based on a detailed clinical assessment (Table 1Table 1
Mutations in Telomerase and Associated Clinical Features of the Six Probands., and Table 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). We used the consensus classification of idiopathic interstitial pneumonia in individual cases.27 At the time the registry was accessed, all 73 probands were reported by their clinicians to be North Americans of European descent.Sequence Analysis
Genomic DNA was isolated from peripheral blood with the use of standard methods. We amplified and sequenced hTR in both directions, as described previously.21 We amplified and sequenced the 16 exons of hTERT and its 3' untranslated region with the use of primers listed in Table 2 of the Supplementary Appendix. Amplicons of hTERT were sequenced in one direction, and suspected changes were confirmed in the opposite strand. Mutations in the probands and their relatives were confirmed by bidirectional sequencing. Sequences were inspected manually with the use of Sequencher software, and variants were compared with public databases. Coding and noncoding variants are listed in Table 3 of the Supplementary Appendix.
Telomeres and Telomerase
A reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay was performed with the use of RNA isolated from peripheral blood to make complementary DNA (cDNA). Primers were designed to span exons where a mutation was predicted to alter splicing; primer sequences are available on request. PCR products were cloned, and the sequence was verified.
The average length of telomeres was measured in peripheral-blood lymphocytes by flow fluorescence in situ hybridization (FISH), as described previously.28
Point mutations were generated, and the telomerase complex was reconstituted in vitro.24 Telomerase activity was assayed without amplification, with the use of a modified direct assay.29,30
Results
Mutations Affecting Telomerase Components
Of 73 probands who were screened, 6 (8%) had heterozygous mutations in hTERT or hTR. Five probands had mutations in hTERT (two missense, two splice junction, and one frameshift), and one proband had a mutation in hTR (Table 1, and Figure 1 of the Supplementary Appendix). None of the hTERT mutations were present in 623 unaffected subjects, as determined in other studies.23,31 Of these subjects, 140 described themselves as white, with the rest describing themselves as black, Hispanic, or Asian. The hTR mutation was also absent in 194 healthy controls. Of these subjects, 123 described themselves as white, with the remaining subjects describing themselves as black, Hispanic, or Asian.22
Mutations Associated with Disease and Short Telomeres
To determine whether telomerase mutations segregated with idiopathic pulmonary fibrosis in families, we examined the pedigrees. The pattern of inheritance was consistent with autosomal dominant inheritance of the disease (Figure 1Figure 1
Pedigrees of Six Probands with Telomerase Mutations.). The mutant allele was present in affected subjects and was generally absent in asymptomatic subjects of the same generation. We identified mutation carriers who did not have symptoms of the disease. These subjects were on average 11 years younger than the probands at the time of diagnosis (Figure 1). This observation is consistent with the variable penetrance associated with familial idiopathic pulmonary fibrosis and also suggests that the onset of disease may be age dependent.To assess whether mutant telomerase is associated with short telomeres, we measured the telomere length in lymphocytes. The average telomere length was significantly less in the probands and asymptomatic mutation carriers than in their relatives who did not carry the mutation (P=0.006) (Figure 2AFigure 2
Telomere Length in Mutation Carriers and Their Relatives.). A comparison of the telomere length in mutation carriers with that in 400 healthy controls, according to age,23 showed that mutation carriers fell below the 10th percentile of the controls (P=0.018), whereas their relatives who were noncarriers clustered near the median (P=0.575) (Figure 2B). Mutant telomerase was therefore associated with short telomeres.Impaired Activity of Mutant Telomerase
We next examined the consequences of hTERT and hTR mutations on telomerase function. We first examined the two missense mutations in hTERT, glutamine replacing leucine at residue 55 (Leu55Gln) and methionine replacing threonine at residue 1110 (Thr1110Met). The Leu55Gln substitution identified in the proband of Family A is in a highly conserved region of the N-terminal; an amino acid substitution of Leu55 may alter telomerase RNA binding and thus the catalytic efficiency of telomerase.32 The Thr1110 residue is also highly conserved and lies in the C-terminal of hTERT, a domain that is thought to mediate recruitment of telomerase to the telomere.33 Both mutant versions of hTERT (Leu55Gln and Thr1110Met) had impaired activity, as compared with the wild-type enzyme (Figure 3C and 3DFigure 3
Biochemical Consequences of Telomerase Mutations in Probands.). Since heterozygous mutations sometimes interfere with the function of the wild-type allele, we assayed the telomerase activity of a mixture of wild-type and mutant versions of the enzyme and observed no dominant negative effect (data not shown).We also examined the effect of the hTR 98 G→A substitution (observed in the proband of Family F) on telomerase activity. This mutation is predicted to impair base pairing in a helix in the essential pseudoknot domain of hTR.34 Moreover, since 98G is conserved in telomerase RNA in all vertebrates, a mutation at this site is expected to alter activity.34 When telomerase was reconstituted with the mutant hTR 98A allele, activity was severely impaired (Figure 3C and 3D).
We next examined the potential consequences of the three mutations in hTERT. The deletion of nucleotide C at codon 112 in the proband of Family C leads to a frameshift mutation and is predicted to result in a nonfunctional, truncated protein. Both splice-junction mutations in Family B and Family D occur at consensus sequences that are conserved in 99.9% of all eukaryotic genes and are therefore predicted to alter splicing. We examined the cDNA of primary cells from a subject in Family D who carried the IVS9-2 A→C mutation and observed skipping of exon 10 but retention of the reading frame (Figure 3E). According to these findings, obtained by RT-PCR, synthesis of a protein of nearly full length is predicted. However, this mutant TERT is predicted to lack an essential motif (the C motif) in the reverse-transcriptase domain and thus to result in a functionally null protein (Figure 3A).8
Clinical Review
We reexamined the probands for the most common features of dyskeratosis congenita. None of the probands had cytopenias (Table 1), and none had any of the classic features of dyskeratosis congenita at the time of diagnosis. To discern whether these six families had hidden cases of dyskeratosis congenita, we requeried family members and medical records for evidence of aplastic anemia. We identified no cases of aplastic anemia in five of the six families. In Family F, we identified three subjects with aplastic anemia and a fourth subject with probable aplastic anemia (Figure 1). In this family, subjects with a hematopoietic defect died at a younger age (25, 26, 31, and 81 years, with a mean of 41 years) than did those with idiopathic pulmonary fibrosis (76, 70, 63, 57, 60, and 66 years, with a mean of 65 years). We also explored the possibility that asymptomatic mutation carriers with short telomeres had cytopenias that reflected early changes of aplastic anemia. We examined complete blood counts in members of five of the families — Family A, Family B, Family C, Family D, and Family E — and found no abnormalities.
To assess whether the pulmonary fibrosis in the probands could be differentiated from other cases of idiopathic pulmonary fibrosis, we reviewed the clinical data. The presentation, age at onset, and findings on computed tomography were indistinguishable from those of other cases of the disease (Table 1 and Figure 4Figure 4
High-Resolution Computed Tomographic Images of the Midlung (Panel A through Panel D) and Bases (Panel E through Panel H) in Probands in Four Families.). None of these subjects had a response to trials of immunosuppressive therapy. In all cases, the proband had undergone lung biopsy, and five of the six probands had the common lesion of usual interstitial pneumonia. A biopsy specimen obtained from the sixth proband showed idiopathic interstitial pneumonia, not classifiable. Different idiopathic interstitial pneumonia pathological lesions have been described in the same patient, as well as in members of the same family with the disease, underscoring the need for precise molecular characterization.4,35 Discussion
We have shown that mutant telomerase is associated with familial idiopathic pulmonary fibrosis, which suggests that the spectrum of disease caused by telomere shortening is more extensive than previously appreciated and that a subgroup of families with pulmonary fibrosis falls on that spectrum.
Short dysfunctional telomeres activate a DNA damage response that leads to cell death or cell-cycle arrest. This response is manifested clinically as organ failure in tissues of high turnover (bone marrow, skin, and gastrointestinal tract) in patients with, and in an animal model of, dyskeratosis congenita.14,24 The presence of pulmonary fibrosis in dyskeratosis congenita, along with the presence of telomerase mutations in some families with idiopathic pulmonary fibrosis, suggests that bronchoalveolar epithelium is also constantly replaced and relies on local progenitor reserves that are limited by short telomeres.
On the basis of these findings, we propose that the fibrotic lesion in patients with short telomeres is provoked by a loss of alveolar cells rather than by a primary fibrogenic process, such as one that would seem to occur in autoimmune disease associated with lung fibrosis. This view is supported by the fact that misfolded surfactant protein C (present in affected subjects carrying a mutation in the corresponding gene) appears to be toxic to alveolar cells.4 Therefore, it is possible that in some types of fibrosis, damage of epithelial cells leads to a remodeling response that appears clinically as usual interstitial pneumonia. Taken together, these considerations may explain the lack of success in reversing idiopathic fibrosis with agents that modulate immune or inflammatory signals and support the idea that at least in some cases, strategies aimed at preventing the loss of alveolar cells, or local responses to such cell loss, may have a greater clinical impact.
Although mutations in the essential components of telomerase do not seem to account for a majority of cases of familial pulmonary fibrosis, telomere shortening as a process may still contribute to the pathogenesis. There is evidence that short telomeres, rather than telomerase mutations, correlate with disease in dyskeratosis congenita. In an animal model of dyskeratosis congenita, wild-type mice who inherit short telomeres appear to have an occult genetic disease and display phenotypes similar to those in mice that are heterozygous for mutant telomerase RNA.14 Acquired states that increase tissue turnover are also associated with short telomeres. One study showed that both current and former smokers had shorter telomeres than did age-matched nonsmokers.36 In addition, there is some evidence that telomeres of the alveolar epithelium in smokers are shorter than those of the alveolar epithelium in nonsmokers.37 It is therefore possible that somatic telomere shortening, caused by conditions that increase cell turnover (e.g., smoking), could contribute to fibrosis. In a study evaluating disease onset in relatives of familial probands with idiopathic pulmonary fibrosis, cigarette smoking and older age were the strongest predictors.35 Because telomere shortening occurs with aging and can be acquired, it may contribute to the disease pathogenesis even in persons with wild-type telomerase.
Our study will have clinical implications, assuming that our findings are replicated by other investigators. As suggested by the experience in aplastic anemia,23 patients who carry either hTERT or hTR mutations are unlikely to have a response to immunosuppression and may be good candidates for investigational clinical trials. The presence of a diagnostic genetic test gives patients at risk and their clinicians a chance to consider early screening and evaluation tailored to identification of complications of dyskeratosis congenita. Patients with dyskeratosis congenita, especially those with severe forms, have a predisposition to cancers of the skin, hematopoietic system, and oral mucosa.
Finally, telomere length may serve as a surrogate marker for the identification of patients at greatest risk for carrying mutant telomerase genes. In our series of 15 subjects, longer telomeres appeared to predict the absence of a telomerase mutation, although this finding requires verification in larger studies. Since the consequences of carrying mutant telomerase genes can appear in adulthood as either idiopathic pulmonary fibrosis or aplastic anemia without dyskeratosis, the consideration of such cases as part of a syndrome of telomere shortening may heighten the index of suspicion and facilitate diagnosis.
Supported by a grant (NCI K08 118416) from the National Institutes of Health (NIH) (to Dr. Armanios), the Richard C. Ross Johns Hopkins School of Medicine Clinician Scientist Award (to Dr. Armanios), the Maryland Cigarette Restitution Fund (to Johns Hopkins University), a grant from the Johns Hopkins Institute for Cellular Engineering Pilot Program (to Dr. Greider), a grant (HL K08 85406) from the NIH and the Francis Family Foundation (to Dr. Lawson), a grant (AI29524) from the NIH and grants (MOP38075 and GMH79042) from the Canadian Institute of Health Research (to Dr. Lansdorp), a Vanderbilt Discovery Grant and the Rudy W. Jacobson endowment (to Dr. Loyd), and a grant (M01 RR-00095) from the National Center for Research Resources of the NIH to support the Vanderbilt Clinical Research Center.
Dr. Lansdorp reports being a founding shareholder in Repeat Diagnostics, a company that specializes in length measurement of leukocyte telomeres with the use of flow FISH. No other potential conflict of interest relevant to this article was reported.
We thank the subjects and their families who participated in this study and their clinicians, especially Drs. Adaani Frost and Keith E. Kelly and nurses Wendi Mason and Rhonda Greer; the Johns Hopkins Fragment Analysis Laboratory and Laura Kasch-Semenza for their help with DNA sequencing; Melissa Prince for technical assistance; and Dr. David Valle for his valuable advice.
Source Information
From the Department of Oncology (M.Y.A., C.W.G.), the Graduate Program in Cellular and Molecular Medicine (J.K.A.), the Institute of Genetic Medicine (R.G.I.), and the Department of Molecular Biology and Genetics (C.W.G.), Johns Hopkins University School of Medicine, Baltimore; the Department of Chemistry and Biochemistry (J.J.-L.C., M.X.) and the School of Life Sciences (J.J.-L.C.), Arizona State University, Tempe; the Departments of Pediatrics (J.D.C., J.A.P.) and Medicine (C.M., W.E.L., J.E.L.), Vanderbilt University School of Medicine, Nashville; the Veterans Affairs Medical Center, Nashville (W.E.L.); and the Terry Fox Laboratory (I.V., P.M.L.) and the British Columbia Cancer Agency and the Department of Medicine (P.M.L.), University of British Columbia, Vancouver, BC, Canada.
Address reprint requests to Dr. Armanios at the Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St., CRB 186, Baltimore, MD 21231, or at marmani1@jhmi.edu.
- References
References
1
Lawson WE ,Loyd JE . The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease? Proc Am Thorac Soc 2006;3:345-349
CrossRef | Medline2
Loyd JE . Pulmonary fibrosis in families. Am J Respir Cell Mol Biol 2003;29:Suppl:S47-S50
Web of Science | Medline3
Marshall RP ,Puddicombe A ,Cookson WO ,Laurent GJ . Adult familial cryptogenic fibrosing alveolitis in the United Kingdom. Thorax 2000;55:143-146
CrossRef | Web of Science | Medline4
Thomas AQ ,Lane K ,Phillips J III , et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002;165:1322-1328
CrossRef | Web of Science | Medline5
Greider CW ,Blackburn EH . Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985;43:405-413
CrossRef | Web of Science | Medline6
Greider CW ,Blackburn EH . A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 1989;337:331-337
CrossRef | Web of Science | Medline7
Nakamura TM ,Morin GB ,Chapman KB , et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997;277:955-959
CrossRef | Web of Science | Medline8
Lingner J ,Hughes TR ,Shevchenko A ,Mann M ,Lundblad V ,Cech TR . Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 1997;276:561-567
CrossRef | Web of Science | Medline9
Harley CB ,Futcher AB ,Greider CW . Telomeres shorten during ageing of human fibroblasts. Nature 1990;345:458-460
CrossRef | Web of Science | Medline10
Vaziri H ,Dragowska W ,Allsopp RC ,Thomas TE ,Harley CB ,Lansdorp PM . Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A 1994;91:9857-9860
CrossRef | Web of Science | Medline11
Lee HW ,Blasco MA ,Gottlieb GJ ,Horner JW II ,Greider CW ,DePinho RA . Essential role of mouse telomerase in highly proliferative organs. Nature 1998;392:569-574
CrossRef | Web of Science | Medline12
d'Adda di Fagagna F ,Reaper PM ,Clay-Farrace L , et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003;426:194-198
CrossRef | Web of Science | Medline13
Hemann MT ,Strong MA ,Hao LY ,Greider CW . The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 2001;107:67-77
CrossRef | Web of Science | Medline14
Hao LY ,Armanios M ,Strong MA , et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 2005;123:1121-1131
CrossRef | Web of Science | Medline15
Rudolph KL ,Chang S ,Lee HW , et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999;96:701-712
CrossRef | Web of Science | Medline16
Dokal I ,Vulliamy T . Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev 2003;17:217-225
CrossRef | Web of Science | Medline17
Dokal I . Dyskeratosis congenita in all its forms. Br J Haematol 2000;110:768-779
CrossRef | Web of Science | Medline18
Knight S ,Vulliamy T ,Copplestone A ,Gluckman E ,Mason P ,Dokal I . Dyskeratosis Congenita (DC) Registry: identification of new features of DC. Br J Haematol 1998;103:990-996
CrossRef | Web of Science | Medline19
Heiss NS ,Knight SW ,Vulliamy TJ , et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998;19:32-38
CrossRef | Web of Science | Medline20
Fogarty PF ,Yamaguchi H ,Wiestner A , et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 2003;362:1628-1630
CrossRef | Web of Science | Medline21
Vulliamy T ,Marrone A ,Goldman F , et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001;413:432-435
CrossRef | Web of Science | Medline22
Yamaguchi H ,Baerlocher GM ,Lansdorp PM , et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 2003;102:916-918
CrossRef | Web of Science | Medline23
Yamaguchi H ,Calado RT ,Ly H , et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005;352:1413-1424
Full Text | Web of Science | Medline24
Armanios M ,Chen JL ,Chang YP , et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005;102:15960-15964
CrossRef | Web of Science | Medline25
Vulliamy T ,Marrone A ,Szydlo R ,Walne A ,Mason PJ ,Dokal I . Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004;36:447-449
CrossRef | Web of Science | Medline26
Blasco MA ,Lee HW ,Hande MP , et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997;91:25-34
CrossRef | Web of Science | Medline27
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304[Erratum, Am J Respir Crit Care Med 2002;166:426.]
Medline28
Baerlocher GM, Vulto V, de Jong G, Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc (in press).
29
Chen JL ,Greider CW . Template boundary definition in mammalian telomerase. Genes Dev 2003;17:2747-2752
CrossRef | Web of Science | Medline30
Drosopoulos WC ,Direnzo R ,Prasad VR . Human telomerase RNA template sequence is a determinant of telomere repeat extension rate. J Biol Chem 2005;280:32801-32810
CrossRef | Web of Science | Medline31
National Institute of Environmental Health Sciences. TERT: telomerase reverse transcriptase. (Accessed March 5, 2007, at http://egp.gs.washington.edu/data/tert/.)
32
Jacobs SA ,Podell ER ,Cech TR . Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat Struct Mol Biol 2006;13:218-225
CrossRef | Web of Science | Medline33
Autexier C ,Lue NF . The structure and function of telomerase reverse transcriptase. Annu Rev Biochem 2006;75:493-517
CrossRef | Web of Science | Medline34
Chen JL ,Blasco MA ,Greider CW . Secondary structure of vertebrate telomerase RNA. Cell 2000;100:503-514
CrossRef | Web of Science | Medline35
Steele MP ,Speer MC ,Loyd JE , et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med 2005;172:1146-1152
CrossRef | Web of Science | Medline36
Valdes AM ,Andrew T ,Gardner JP , et al. Obesity, cigarette smoking, and telomere length in women. Lancet 2005;366:662-664
CrossRef | Web of Science | Medline37
Tsuji T ,Aoshiba K ,Nagai A . Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 2006;174:886-893
CrossRef | Web of Science | Medline
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CrossRef2
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CrossRef3
Mary Armanios. (2012) Telomerase and idiopathic pulmonary fibrosis. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 730:1-2, 52-58
CrossRef4
Joshua D. Podlevsky, Julian J.-L. Chen. (2012) It all comes together at the ends: Telomerase structure, function, and biogenesis. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 730:1-2, 3-11
CrossRef5
Nya D. Nelson, Alison A. Bertuch. (2012) Dyskeratosis congenita as a disorder of telomere maintenance. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 730:1-2, 43-51
CrossRef6
Jean Ann Maguire, Surafel Mulugeta, Michael F. Beers. (2012) Multiple ways to die: Delineation of the unfolded protein response and apoptosis induced by Surfactant Protein C BRICHOS mutants. The International Journal of Biochemistry & Cell Biology 44:1, 101-112
CrossRef7
R. Schmitt. (2011) Mechanismen der renalen Fibrose. Der Nephrologe
CrossRef8
M. Mihalusova, J. Y. Wu, X. Zhuang. (2011) Telomerase and Retrotransposons: Reverse Transcriptases That Shaped Genomes Special Feature Sackler Colloquium: Functional importance of telomerase pseudoknot revealed by single-molecule analysis. Proceedings of the National Academy of Sciences 108:51, 20339-20344
CrossRef9
Q. Zhang, N.-K. Kim, J. Feigon. (2011) Telomerase and Retrotransposons: Reverse Transcriptases That Shaped Genomes Special Feature Sackler Colloquium: Architecture of human telomerase RNA. Proceedings of the National Academy of Sciences 108:51, 20325-20332
CrossRef10
Tobias Sperka, Zhangfa Song, Yohei Morita, Kodandaramireddy Nalapareddy, Luis Miguel Guachalla, André Lechel, Yvonne Begus-Nahrmann, Martin D. Burkhalter, Monika Mach, Falk Schlaudraff, Birgit Liss, Zhenyu Ju, Michael R. Speicher, K. Lenhard Rudolph. (2011) Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction. Nature Cell Biology 14:1, 73-79
CrossRef11
Nadia Nathan, Guillaume Thouvenin, Brigitte Fauroux, Harriet Corvol, Annick Clement. (2011) Interstitial lung disease: Physiopathology in the context of lung growth. Paediatric Respiratory Reviews 12:4, 216-222
CrossRef12
Talmadge E King, Annie Pardo, Moisés Selman. (2011) Idiopathic pulmonary fibrosis. The Lancet 378:9807, 1949-1961
CrossRef13
Yurdagül Uzunhan, Hilario Nunes, Thomas Gille, Camille Bron, Carole Planès, Dominique Valeyre. (2011) Innovations thérapeutiques de la fibrose pulmonaire idiopathique. La Presse Médicale 40:12, 1100-1112
CrossRef14
Megan Stuebner Devine, Christine Kim Garcia. (2011) Genetic Interstitial Lung Disease. Clinics in Chest Medicine
CrossRef15
Philip J. Mason, Monica Bessler. (2011) The genetics of dyskeratosis congenita. Cancer Genetics 204:12, 635-645
CrossRef16
Päivi M. Järvinen, Marikki Laiho. (2011) LIM-domain proteins in transforming growth factor β-induced epithelial-to-mesenchymal transition and myofibroblast differentiation. Cellular Signalling
CrossRef17
P. G. Surtees, N. W. J. Wainwright, K. A. Pooley, R. N. Luben, K.-T. Khaw, D. F. Easton, A. M. Dunning. (2011) Life Stress, Emotional Health, and Mean Telomere Length in the European Prospective Investigation into Cancer (EPIC)-Norfolk Population Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 66A:11, 1152-1162
CrossRef18
S. Adnot, N. Frossard, S. Adnot, E. Artaud-Macari. (2011) Sénescence cellulaire et télomères dans les maladies respiratoires. Revue des Maladies Respiratoires Actualités 3:3, 202-207
CrossRef19
Daniel J. Kass, Naftali Kaminski. (2011) Evolving Genomic Approaches to Idiopathic Pulmonary Fibrosis: Moving Beyond Genes. Clinical and Translational Science 4:5, 372-379
CrossRef20
Downey, Gregory P., . (2011) Resolving the Scar of Pulmonary Fibrosis. New England Journal of Medicine 365:12, 1140-1141
Full Text21
B. Crestani, Yurdagül Uzunhan. (2011) Physiopathologie de la fibrose pulmonaire idiopathique (FPI). Revue des Maladies Respiratoires Actualités 3, S109-S110
CrossRef22
Marta Gladych, Aneta Wojtyla, Blazej Rubis. (2011) Human telomerase expression regulation. Biochemistry and Cell Biology 89:4, 359-376
CrossRef23
Bruno Bernardes de Jesus, Kerstin Schneeberger, Elsa Vera, Agueda Tejera, Calvin B. Harley, Maria A. Blasco. (2011) The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 10:4, 604-621
CrossRef24
Charles C. Chung, Stephen J. Chanock. (2011) Current status of genome-wide association studies in cancer. Human Genetics 130:1, 59-78
CrossRef25
H. Nunes, Y. Uzunhan. (2011) Pneumopathies interstitielles diffuses. Revue des Maladies Respiratoires Actualités 3:6, 113-127
CrossRef26
Moisés Selman, Annie Pardo, Luca Richeldi, Stefania Cerri. (2011) Emerging drugs for idiopathic pulmonary fibrosis. Expert Opinion on Emerging Drugs 16:2, 341-362
CrossRef27
Donald F. Zoz, William E. Lawson, Timothy S. Blackwell. (2011) Idiopathic Pulmonary Fibrosis: A Disorder of Epithelial Cell Dysfunction. The American Journal of the Medical Sciences 341:6, 435-438
CrossRef28
William E. Lawson, James E. Loyd, Amber L. Degryse. (2011) Genetics in Pulmonary Fibrosis—Familial Cases Provide Clues to the Pathogenesis of Idiopathic Pulmonary Fibrosis. The American Journal of the Medical Sciences 341:6, 439-443
CrossRef29
E. M. Parry, J. K. Alder, X. Qi, J. J.- L. Chen, M. Armanios. (2011) Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117:21, 5607-5611
CrossRef30
Daniel Hartmann, Ujala Srivastava, Michaela Thaler, Karin N. Kleinhans, Gisèle N'Kontchou, Annika Scheffold, Kerstin Bauer, Ramona F. Kratzer, Natalia Kloos, Sarah-Fee Katz, Zhangfa Song, Yvonne Begus-Nahrmann, Alexander Kleger, Guido von Figura, Pavel Strnad, André Lechel, Cagatay Günes, Andrej Potthoff, Katja Deterding, Heiner Wedemeyer, Zhenyu Ju, Ge Song, Feng Xiao, Sonja Gillen, Hubert Schrezenmeier, Thomas Mertens, Marianne Ziol, Helmut Friess, Michael Jarek, Michael P. Manns, Michel Beaugrand, K. Lenhard Rudolph. (2011) Telomerase gene mutations are associated with cirrhosis formation. Hepatology 53:5, 1608-1617
CrossRef31
Rodrigo T. Calado, Jennifer Brudno, Paulomi Mehta, Joseph J. Kovacs, Colin Wu, Marco A. Zago, Stephen J. Chanock, Thomas D. Boyer, Neal S. Young. (2011) Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 53:5, 1600-1607
CrossRef32
Boucher, Richard C., . (2011) Idiopathic Pulmonary Fibrosis — A Sticky Business. New England Journal of Medicine 364:16, 1560-1561
Full Text33
Seibold, Max A., Wise, Anastasia L., Speer, Marcy C., Steele, Mark P., Brown, Kevin K., Loyd, James E., Fingerlin, Tasha E., Zhang, Weiming, Gudmundsson, Gunnar, Groshong, Steve D., Evans, Christopher M., Garantziotis, Stavros, Adler, Kenneth B., Dickey, Burton F., du Bois, Roland M., Yang, Ivana V., Herron, Aretha, Kervitsky, Dolly, Talbert, Janet L., Markin, Cheryl, Park, Joungjoa, Crews, Anne L., Slifer, Susan H., Auerbach, Scott, Roy, Michelle G., Lin, Jia, Hennessy, Corinne E., Schwarz, Marvin I., Schwartz, David A., . (2011) A Common MUC5B Promoter Polymorphism and Pulmonary Fibrosis. New England Journal of Medicine 364:16, 1503-1512
Full Text34
Andrea T. Borchers, Christopher Chang, Carl L. Keen, M. Eric Gershwin. (2011) Idiopathic Pulmonary Fibrosis—an Epidemiological and Pathological Review. Clinical Reviews in Allergy & Immunology 40:2, 117-134
CrossRef35
Erin M. Buckingham, Aloysius J. Klingelhutz. (2011) The role of telomeres in the ageing of human skin. Experimental Dermatology 20:4, 297-302
CrossRef36
Darryl Knight, Steven E. Mutsaers, Cecilia M. Prêle. (2011) STAT3 in tissue fibrosis: Is there a role in the lung?. Pulmonary Pharmacology & Therapeutics 24:2, 193-198
CrossRef37
Max A. Seibold, David A. Schwartz. (2011) The Lung: The Natural Boundary Between Nature and Nurture. Annual Review of Physiology 73:1, 457-478
CrossRef38
Jillian E. Koziel, Melanie J. Fox, Catherine E. Steding, Alyssa A. Sprouse, Brittney-Shea Herbert. (2011) Medical genetics and epigenetics of telomerase. Journal of Cellular and Molecular Medicine 15:3, 457-467
CrossRef39
Paula Martínez, María A. Blasco. (2011) Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nature Reviews Cancer 11:3, 161-176
CrossRef40
Julien Hadoux, Benjamin Besse, David Planchard. (2011) Cancers bronchiques des non-fumeurs : particularités épidémiologiques, thérapeutiques et moléculaires. La Presse Médicale
CrossRef41
Calvin B. Harley, Weimin Liu, Maria Blasco, Elsa Vera, William H. Andrews, Laura A. Briggs, Joseph M. Raffaele. (2011) A Natural Product Telomerase Activator As Part of a Health Maintenance Program. Rejuvenation Research 14:1, 45-56
CrossRef42
Tal Biron-Shental, Dvora Kidron, Rivka Sukenik-Halevy, Lilach Goldberg-Bittman, Reuven Sharony, Moshe D. Fejgin, Aliza Amiel. (2011) TERC telomerase subunit gene copy number in placentas from pregnancies complicated with intrauterine growth restriction. Early Human Development 87:2, 73-75
CrossRef43
Kazuhiro USUI, Chiharu TANAI, Yoshiaki TANAKA, Hiromichi NODA, Teruo ISHIHARA. (2011) The prevalence of pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology 16:2, 326-331
CrossRef44
L. E. Donate, M. A. Blasco. (2011) Telomeres in cancer and ageing. Philosophical Transactions of the Royal Society B: Biological Sciences 366:1561, 76-84
CrossRef45
Antonio Paolo Beltrami, Daniela Cesselli, Carlo Alberto Beltrami. (2011) At the stem of youth and health. Pharmacology & Therapeutics 129:1, 3-20
CrossRef46
Ahmed Fahim, Michael Crooks, Simon P. Hart. (2011) Gastroesophageal Reflux and Idiopathic Pulmonary Fibrosis: A Review. Pulmonary Medicine 2011, 1-7
CrossRef47
Neelam Giri, Rees Lee, Albert Faro, Charles B Huddleston, Frances V White, Blanche P Alter, Sharon A Savage. (2011) Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC Blood Disorders 11:1, 3
CrossRef48
Bryan Corrin, Andrew G. Nicholson. 2011. Diffuse parenchymal disease of the lung. , 263-326.
CrossRef49
Payal K Naik, Bethany B Moore. (2010) Viral infection and aging as cofactors for the development of pulmonary fibrosis. Expert Review of Respiratory Medicine 4:6, 759-771
CrossRef50
Sharon A. Savage, Alison A. Bertuch. (2010) The genetics and clinical manifestations of telomere biology disorders. Genetics in Medicine 12:12, 753-764
CrossRef51
N. S. Young. (2010) Telomere Biology and Telomere Diseases: Implications for Practice and Research. Hematology 2010:1, 30-35
CrossRef52
Robert J Homer, Erica L Herzog. (2010) Recent advances in pulmonary fibrosis: implications for scleroderma. Current Opinion in Rheumatology 22:6, 683-689
CrossRef53
Nathaniel Rothman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Nuria Malats, Xifeng Wu, Jonine D Figueroa, Francisco X Real, David Van Den Berg, Giuseppe Matullo, Dalsu Baris, Michael Thun, Lambertus A Kiemeney, Paolo Vineis, Immaculata De Vivo, Demetrius Albanes, Mark P Purdue, Thorunn Rafnar, Michelle A T Hildebrandt, Anne E Kiltie, Olivier Cussenot, Klaus Golka, Rajiv Kumar, Jack A Taylor, Jose I Mayordomo, Kevin B Jacobs, Manolis Kogevinas, Amy Hutchinson, Zhaoming Wang, Yi-Ping Fu, Ludmila Prokunina-Olsson, Laurie Burdett, Meredith Yeager, William Wheeler, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Alison Johnson, Molly Schwenn, Margaret R Karagas, Alan Schned, Gerald Andriole, Robert Grubb, Amanda Black, Eric J Jacobs, W Ryan Diver, Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, Victoria K Cortessis, Manuela Gago-Dominguez, Malcolm C Pike, Mariana C Stern, Jian-Min Yuan, David J Hunter, Monica McGrath, Colin P Dinney, Bogdan Czerniak, Meng Chen, Hushan Yang, Sita H Vermeulen, Katja K Aben, J Alfred Witjes, Remco R Makkinje, Patrick Sulem, Soren Besenbacher, Kari Stefansson, Elio Riboli, Paul Brennan, Salvatore Panico, Carmen Navarro, Naomi E Allen, H Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Neil Caporaso, Maria Teresa Landi, Federico Canzian, Borje Ljungberg, Anne Tjonneland, Francoise Clavel-Chapelon, David T Bishop, Mark T W Teo, Margaret A Knowles, Simonetta Guarrera, Silvia Polidoro, Fulvio Ricceri, Carlotta Sacerdote, Alessandra Allione, Geraldine Cancel-Tassin, Silvia Selinski, Jan G Hengstler, Holger Dietrich, Tony Fletcher, Peter Rudnai, Eugen Gurzau, Kvetoslava Koppova, Sophia C E Bolick, Ashley Godfrey, Zongli Xu, José I Sanz-Velez, María D García-Prats, Manuel Sanchez, Gabriel Valdivia, Stefano Porru, Simone Benhamou, Robert N Hoover, Joseph F Fraumeni, Debra T Silverman, Stephen J Chanock. (2010) A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nature Genetics 42:11, 978-984
CrossRef54
Inderjeet S Dokal. 2010. Inherited Aplastic Anaemia/Bone Marrow Failure Syndromes. , 186-205.
CrossRef55
Nobuhiro Nishio, Seiji Kojima. (2010) Recent progress in dyskeratosis congenita. International Journal of Hematology 92:3, 419-424
CrossRef56
Paula Martínez, Maria A. Blasco. (2010) Role of shelterin in cancer and aging. Aging Cell 9:5, 653-666
CrossRef57
Rosario Perona. (2010) The Nobel Prize in Physiology or Medicine 2009 “for telomere biology” and its relevance to cancer and related diseases. Clinical and Translational Oncology 12:10, 647-649
CrossRef58
Jing Ye, Yunlin Wu, Eric Gilson. (2010) Dynamics of telomeric chromatin at the crossroads of aging and cancer. Essays in Biochemistry 48:1, 147-164
CrossRef59
Nuno M.V. Gomes, Jerry W. Shay, Woodring E. Wright. (2010) Telomere biology in Metazoa. FEBS Letters 584:17, 3741-3751
CrossRef60
H. D. M. Wyatt, S. C. West, T. L. Beattie. (2010) InTERTpreting telomerase structure and function. Nucleic Acids Research 38:17, 5609-5622
CrossRef61
Lisa Mirabello, Kai Yu, Peter Kraft, Immaculata De Vivo, David J. Hunter, Jennifer Prescott, Jason Y.Y. Wong, Nilanjan Chatterjee, Richard B. Hayes, Sharon A. Savage. (2010) The association of telomere length and genetic variation in telomere biology genesa. Human Mutation 31:9, 1050-1058
CrossRef62
Monica Bessler, David B. Wilson, Philip J. Mason. (2010) Dyskeratosis congenita. FEBS Letters 584:17, 3831-3838
CrossRef63
Paula Martinez, Maria Thanasoula, Ana R. Carlos, Gonzalo Gómez-López, Agueda M. Tejera, Stefan Schoeftner, Orlando Dominguez, David G. Pisano, Madalena Tarsounas, Maria A. Blasco. (2010) Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nature Cell Biology 12:8, 768-780
CrossRef64
Sophie Georgin-Lavialle, Achille Aouba, Luc Mouthon, J. Arturo Londono-Vallejo, Yves Lepelletier, Anne-Sophie Gabet, Olivier Hermine. (2010) The telomere/telomerase system in autoimmune and systemic immune-mediated diseases. Autoimmunity Reviews 9:10, 646-651
CrossRef65
Maria Molina-Molina, Vanesa Vicens, Susanna Estany. (2010) New Aspects of Idiopathic Pulmonary Fibrosis. Clinical Pulmonary Medicine 17:4, 170-176
CrossRef66
D. Levy, S. L. Neuhausen, S. C. Hunt, M. Kimura, S.-J. Hwang, W. Chen, J. C. Bis, A. L. Fitzpatrick, E. Smith, A. D. Johnson, J. P. Gardner, S. R. Srinivasan, N. Schork, J. I. Rotter, U. Herbig, B. M. Psaty, M. Sastrasinh, S. S. Murray, R. S. Vasan, M. A. Province, N. L. Glazer, X. Lu, X. Cao, R. Kronmal, M. Mangino, N. Soranzo, T. D. Spector, G. S. Berenson, A. Aviv. (2010) Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proceedings of the National Academy of Sciences 107:20, 9293-9298
CrossRef67
Agueda M. Tejera, Martina Stagno d'Alcontres, Maria Thanasoula, Rosa M. Marion, Paula Martinez, Chunyan Liao, Juana M. Flores, Madalena Tarsounas, Maria A. Blasco. (2010) TPP1 Is Required for TERT Recruitment, Telomere Elongation during Nuclear Reprogramming, and Normal Skin Development in Mice. Developmental Cell 18:5, 775-789
CrossRef68
Akiko Shimamura, Blanche P. Alter. (2010) Pathophysiology and management of inherited bone marrow failure syndromes. Blood Reviews 24:3, 101-122
CrossRef69
S. Harari, A. Caminati. (2010) IPF: new insight on pathogenesis and treatment. Allergy 65:5, 537-553
CrossRef70
Li-jun Chen, Wan-de Li, Shi-feng Li, Xing-wen Su, Guang-yun Lin, Yi-jun Huang, Guang-mei Yan. (2010) Bleomycin induces upregulation of lysyl oxidase in cultured human fetal lung fibroblasts. Acta Pharmacologica Sinica 31:5, 554-559
CrossRef71
Duncan M. Baird. (2010) Variation at the TERT locus and predisposition for cancer. Expert Reviews in Molecular Medicine 12,
CrossRef72
Eric Gilson, Evelyne Ségal-Bendirdjian. (2010) The telomere story or the triumph of an open-minded research. Biochimie 92:4, 321-326
CrossRef73
L. S.M. Wong, J. Huzen, P. van der Harst, R. A. de Boer, V. Codd, B. Daan Westenbrink, G. F.J.D. Benus, A. A. Voors, W. H. van Gilst, N. J. Samani, T. Jaarsma, D. J. van Veldhuisen. (2010) Anaemia is associated with shorter leucocyte telomere length in patients with chronic heart failure. European Journal of Heart Failure 12:4, 348-353
CrossRef74
Joyce S. Lee, Harold R. Collard, Ganesh Raghu, Matthew P. Sweet, Steven R. Hays, Guilherme M. Campos, Jeffrey A. Golden, Talmadge E. King. (2010) Does Chronic Microaspiration Cause Idiopathic Pulmonary Fibrosis?. The American Journal of Medicine 123:4, 304-311
CrossRef75
Rosa M Marión, Maria A Blasco. (2010) Telomere rejuvenation during nuclear reprogramming. Current Opinion in Genetics & Development 20:2, 190-196
CrossRef76
M. Xie, J. D. Podlevsky, X. Qi, C. J. Bley, J. J. L. Chen. (2010) A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity. Nucleic Acids Research 38:6, 1982-1996
CrossRef77
Ergün Sahin, Ronald A. DePinho. (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464:7288, 520-528
CrossRef78
A. D. Irvine, J. E. Mellerio. 2010. Genetics and Genodermatoses. , 1-97.
CrossRef79
F. Qiao, K. J. Goodrich, T. R. Cech. (2010) Engineering cis-telomerase RNAs that add telomeric repeats to themselves. Proceedings of the National Academy of Sciences 107:11, 4914-4918
CrossRef80
Lawrence M. Nogee. (2010) Genetic Basis of Children's Interstitial Lung Disease. Pediatric Allergy, Immunology, and Pulmonology 23:1, 15-24
CrossRef81
Daniel Reis Waisberg, João Valente Barbas-Filho, Edwin Roger Parra, Sandra Fernezlian, Carlos Roberto Ribeiro de Carvalho, Ronaldo Adib Kairalla, Vera Luiza Capelozzi. (2010) Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis. Human Pathology 41:3, 385-391
CrossRef82
Stavros Garantziotis, David A. Schwartz. (2010) Ecogenomics of Respiratory Diseases of Public Health Significance. Annual Review of Public Health 31:1, 37-51
CrossRef83
Roderick J. O'Sullivan, Jan Karlseder. (2010) Telomeres: protecting chromosomes against genome instability. Nature Reviews Molecular Cell Biology
CrossRef84
Jeffrey A. Whitsett, Susan E. Wert, Timothy E. Weaver. (2010) Alveolar Surfactant Homeostasis and the Pathogenesis of Pulmonary Disease. Annual Review of Medicine 61:1, 105-119
CrossRef85
Lawrence M. Nogee. (2010) Genetic Basis of Children’s Interstitial Lung Disease. Pediatric Allergy, Immunology, and Pulmonology110525163459060
CrossRef86
Kristen L. Veraldi, Eileen Hsu, Carol A. Feghali-Bostwick. (2010) Pathogenesis of Pulmonary Fibrosis in Systemic Sclerosis: Lessons from Interstitial Lung Disease. Current Rheumatology Reports 12:1, 19-25
CrossRef87
R. M. du Bois. (2010) Strategies for treating idiopathic pulmonary fibrosis. Nature Reviews Drug Discovery 9:2, 129-140
CrossRef88
C. C. Chung, W. C. S. Magalhaes, J. Gonzalez-Bosquet, S. J. Chanock. (2010) Genome-wide association studies in cancer--current and future directions. Carcinogenesis 31:1, 111-120
CrossRef89
Jeffrey T. Chapman. (2010) Crucial Communications. Seminars in Roentgenology 45:1, 4-7
CrossRef90
Sandy Mattijssen, Tim J. M. Welting, Ger J. M. Pruijn. (2010) RNase MRP and disease. Wiley Interdisciplinary Reviews - RNAn/a-n/a
CrossRef91
Hong Jiang, Wenqing Chen, Lihui Qu, Ying Chen, Qiang He, Huiping Wang, Jianyong Wu, Zhangfei Shou, Zhenyu Ju, Jianghua Chen. (2010) ELISA for Aging Biomarkers Induced by Telomere Dysfunction in Human Plasma. Journal of Biomedicine and Biotechnology 2010, 1-4
CrossRef92
George R. Washko, David A. Lynch, Shin Matsuoka, James C. Ross, Shigeaki Umeoka, Alejandro Diaz, Frank C. Sciurba, Gary M. Hunninghake, Raúl San José Estépar, Edwin K. Silverman, Ivan O. Rosas, Hiroto Hatabu. (2010) Identification of Early Interstitial Lung Disease in Smokers from the COPDGene Study. Academic Radiology 17:1, 48-53
CrossRef93
Calado, Rodrigo T., Young, Neal S., . (2009) Telomere Diseases. New England Journal of Medicine 361:24, 2353-2365
Full Text94
Mary Armanios, Jonathan K. Alder, Erin M. Parry, Baktiar Karim, Margaret A. Strong, Carol W. Greider. (2009) Short Telomeres are Sufficient to Cause the Degenerative Defects Associated with Aging. The American Journal of Human Genetics 85:6, 823-832
CrossRef95
Guido von Figura, Daniel Hartmann, Zhangfa Song, Karl Lenhard Rudolph. (2009) Role of telomere dysfunction in aging and its detection by biomarkers. Journal of Molecular Medicine 87:12, 1165-1171
CrossRef96
Michael Kirwan, Tom Vulliamy, Anna Marrone, Amanda J. Walne, Richard Beswick, Peter Hillmen, Richard Kelly, Andrew Stewart, David Bowen, Stefan O. Schonland, Annika Maria Whittle, Anthony McVerry, Maria Gilleece, Inderjeet Dokal. (2009) Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Human Mutation 30:11, 1567-1573
CrossRef97
Jürgen BEHR, Martin KOLB, Gerard COX. (2009) Treating IPF-all or nothing? A PRO-CON debate. Respirology 14:8, 1072-1081
CrossRef98
Maria Teresa Landi, Nilanjan Chatterjee, Kai Yu, Lynn R. Goldin, Alisa M. Goldstein, Melissa Rotunno, Lisa Mirabello, Kevin Jacobs, William Wheeler, Meredith Yeager, Andrew W. Bergen, Qizhai Li, Dario Consonni, Angela C. Pesatori, Sholom Wacholder, Michael Thun, Ryan Diver, Martin Oken, Jarmo Virtamo, Demetrius Albanes, Zhaoming Wang, Laurie Burdette, Kimberly F. Doheny, Elizabeth W. Pugh, Cathy Laurie, Paul Brennan, Rayjean Hung, Valerie Gaborieau, James D. McKay, Mark Lathrop, John McLaughlin, Ying Wang, Ming-Sound Tsao, Margaret R. Spitz, Yufei Wang, Hans Krokan, Lars Vatten, Frank Skorpen, Egil Arnesen, Simone Benhamou, Christine Bouchard, Andres Metsapalu, Tonu Vooder, Mari Nelis, Kristian Välk, John K. Field, Chu Chen, Gary Goodman, Patrick Sulem, Gudmar Thorleifsson, Thorunn Rafnar, Timothy Eisen, Wiebke Sauter, Albert Rosenberger, Heike Bickeböller, Angela Risch, Jenny Chang-Claude, H. Erich Wichmann, Kari Stefansson, Richard Houlston, Christopher I. Amos, Joseph F. Fraumeni, Sharon A. Savage, Pier Alberto Bertazzi, Margaret A. Tucker, Stephen Chanock, Neil E. Caporaso. (2009) A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma. The American Journal of Human Genetics 85:5, 679-691
CrossRef99
Jue Lin, Elissa S. Epel, Elizabeth H. Blackburn. 2009. Telomeres, Telomerase, Stress, and Aging. .
CrossRef100
Cabot, Richard C.Harris, Nancy Lee, Shepard, Jo-Anne O., Rosenberg, Eric S., Cort, Alice M., Ebeling, Sally H.Peters, Christine C., Tager, Andrew M., Sharma, Amita, Mark, Eugene J., . (2009) Case 32-2009. New England Journal of Medicine 361:16, 1585-1593
Full Text101
Peter M Lansdorp. (2009) Telomeres and disease. The EMBO Journal 28:17, 2532-2540
CrossRef102
Mary Armanios. (2009) Syndromes of Telomere Shortening. Annual Review of Genomics and Human Genetics 10:1, 45-61
CrossRef103
Mark Hills, Peter M. Lansdorp. (2009) Short Telomeres Resulting from Heritable Mutations in the Telomerase Reverse Transcriptase Gene Predispose for a Variety of Malignancies. Annals of the New York Academy of Sciences 1176:1, 178-190
CrossRef104
Sharon A. Savage, Inderjeet Dokal, Mary Armanios, Geraldine Aubert, Edward W. Cowen, Demetrio L. Domingo, Neelam Giri, Mark H. Greene, Paul J. Orchard, Jakub Tolar, Ekaterini Tsilou, Carter Van Waes, Judy M.Y. Wong, Neal S. Young, Blanche P. Alter. (2009) Dyskeratosis congenita: The first NIH clinical research workshop. Pediatric Blood & Cancer 53:3, 520-523
CrossRef105
Robert Matthew KOTTMANN, Christopher M. HOGAN, Richard P. PHIPPS, Patricia J. SIME. (2009) Determinants of initiation and progression of idiopathic pulmonary fibrosis. Respirology 14:7, 917-933
CrossRef106
Harriet Corvol, Florence Flamein, Ralph Epaud, Annick Clement, Loic Guillot. (2009) Lung alveolar epithelium and interstitial lung disease. The International Journal of Biochemistry & Cell Biology 41:8-9, 1643-1651
CrossRef107
Yan Liu, Hanna K. Sanoff, Hyunsoon Cho, Christin E. Burd, Chad Torrice, Joseph G. Ibrahim, Nancy E. Thomas, Norman E. Sharpless. (2009) Expression of p16 INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 8:4, 439-448
CrossRef108
John E. HEFFNER, Stephen T. HOLGATE, Kian Fan CHUNG, Michael S. NIEDERMAN, Charles L. DALEY, James R. JETT, John R. STRADLING, Athol U. WELLS, Richard W. LIGHT, Victor F. TAPSON, David M. HANSELL, Peter J. PROVONOST, Y.C. Gary LEE. (2009) Road ahead to respiratory health: Experts chart future research directions. Respirology 14:5, 625-636
CrossRef109
William D. Hardie, Stephan W. Glasser, James S. Hagood. (2009) Emerging Concepts in the Pathogenesis of Lung Fibrosis. The American Journal of Pathology 175:1, 3-16
CrossRef110
M. Hills, K. Lucke, E. A. Chavez, C. J. Eaves, P. M. Lansdorp. (2009) Probing the mitotic history and developmental stage of hematopoietic cells using single telomere length analysis (STELA). Blood 113:23, 5765-5775
CrossRef111
P. Davy, M. Nagata, P. Bullard, N.S. Fogelson, R. Allsopp. (2009) Fetal Growth Restriction is Associated with Accelerated Telomere Shortening and Increased Expression of Cell Senescence Markers in the Placenta. Placenta 30:6, 539-542
CrossRef112
Michael Kirwan, Inderjeet Dokal. (2009) Dyskeratosis congenita, stem cells and telomeres. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1792:4, 371-379
CrossRef113
Sharon A. Savage, Blanche P. Alter. (2009) Dyskeratosis Congenita. Hematology/Oncology Clinics of North America 23:2, 215-231
CrossRef114
Amanda J. Walne, Inderjeet Dokal. (2009) Advances in the understanding of dyskeratosis congenita. British Journal of Haematology 145:2, 164-172
CrossRef115
Alejandro Chavez, Amy M. Tsou, F. Brad Johnson. (2009) Telomeres do the (un)twist: Helicase actions at chromosome termini. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1792:4, 329-340
CrossRef116
Seth L. Masters, Anna Simon, Ivona Aksentijevich, Daniel L. Kastner. (2009) Horror Autoinflammaticus : The Molecular Pathophysiology of Autoinflammatory Disease *. Annual Review of Immunology 27:1, 621-668
CrossRef117
Murielle Mimeault, Surinder K. Batra. (2009) Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications. Ageing Research Reviews 8:2, 94-112
CrossRef118
Rosa M. Marion, Katerina Strati, Han Li, Agueda Tejera, Stefan Schoeftner, Sagrario Ortega, Manuel Serrano, Maria A. Blasco. (2009) Telomeres Acquire Embryonic Stem Cell Characteristics in Induced Pluripotent Stem Cells. Cell Stem Cell 4:2, 141-154
CrossRef119
R. T. Calado, J. A. Regal, M. Hills, W. T. Yewdell, L. F. Dalmazzo, M. A. Zago, P. M. Lansdorp, D. Hogge, S. J. Chanock, E. H. Estey, R. P. Falcao, N. S. Young. (2009) Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proceedings of the National Academy of Sciences 106:4, 1187-1192
CrossRef120
R. T. Calado. (2009) Telomeres and marrow failure. Hematology 2009:1, 338-343
CrossRef121
Yongyu Wang, Phillip J. Kuan, Chao Xing, Jennifer T. Cronkhite, Fernando Torres, Randall L. Rosenblatt, J. Michael DiMaio, Lisa N. Kinch, Nick V. Grishin, Christine Kim Garcia. (2009) Genetic Defects in Surfactant Protein A2 Are Associated with Pulmonary Fibrosis and Lung Cancer. The American Journal of Human Genetics 84:1, 52-59
CrossRef122
Yusuke Nakamura. (2009) DNA variations in human and medical genetics: 25 years of my experience. Journal of Human Genetics 54:1, 1-8
CrossRef123
Scott H. Randell, Kimberlie Burns, Richard C. Boucher. 2009. Epithelial Cells. , 201-210.
CrossRef124
Jessica A. Box, Jeremy T. Bunch, Wen Tang, Peter Baumann. (2008) Spliceosomal cleavage generates the 3′ end of telomerase RNA. Nature 456:7224, 910-914
CrossRef125
R.A. McCord, D. Broccoli. (2008) Telomeric chromatin: Roles in aging, cancer and hereditary disease. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 647:1-2, 86-93
CrossRef126
D. C. Zappulla, J. N. Roberts, K. J. Goodrich, T. R. Cech, D. S. Wuttke. (2008) Inhibition of yeast telomerase action by the telomeric ssDNA-binding protein, Cdc13p. Nucleic Acids Research 37:2, 354-367
CrossRef127
Antonia Tomás-Loba, Ignacio Flores, Pablo J. Fernández-Marcos, María L. Cayuela, Antonio Maraver, Agueda Tejera, Consuelo Borrás, Ander Matheu, Peter Klatt, Juana M. Flores, José Viña, Manuel Serrano, Maria A. Blasco. (2008) Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice. Cell 135:4, 609-622
CrossRef128
H.-Y. Du, E. Pumbo, J. Ivanovich, P. An, R. T. Maziarz, U. M. Reiss, D. Chirnomas, A. Shimamura, A. Vlachos, J. M. Lipton, R. K. Goyal, F. Goldman, D. B. Wilson, P. J. Mason, M. Bessler. (2008) TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements. Blood 113:2, 309-316
CrossRef129
J. K. Alder, J. J.-L. Chen, L. Lancaster, S. Danoff, S.-c. Su, J. D. Cogan, I. Vulto, M. Xie, X. Qi, R. M. Tuder, J. A. Phillips, P. M. Lansdorp, J. E. Loyd, M. Y. Armanios. (2008) Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proceedings of the National Academy of Sciences 105:35, 13051-13056
CrossRef130
Harold Riethman. (2008) Human Telomere Structure and Biology. Annual Review of Genomics and Human Genetics 9:1, 1-19
CrossRef131
H. Jiang, E. Schiffer, Z. Song, J. Wang, P. Zurbig, K. Thedieck, S. Moes, H. Bantel, N. Saal, J. Jantos, M. Brecht, P. Jeno, M. N. Hall, K. Hager, M. P. Manns, H. Hecker, A. Ganser, K. Dohner, A. Bartke, C. Meissner, H. Mischak, Z. Ju, K. L. Rudolph. (2008) Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proceedings of the National Academy of Sciences 105:32, 11299-11304
CrossRef132
Fiorella Calabrese, Cinzia Giacometti, Francesca Lunardi, Marialuisa Valente. (2008) Morphological and molecular markers in idiopathic pulmonary fibrosis. Expert Review of Respiratory Medicine 2:4, 505-520
CrossRef133
Leslie A. Fecher. 2008. Overview of Molecular Pathways inMelanoma. , 9-26.
CrossRef134
Michelle Sabourin, Virginia A. Zakian. (2008) ATM-like kinases and regulation of telomerase: lessons from yeast and mammals. Trends in Cell Biology 18:7, 337-346
CrossRef135
T. Vulliamy, R. Beswick, M. Kirwan, A. Marrone, M. Digweed, A. Walne, I. Dokal. (2008) From the Cover: Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proceedings of the National Academy of Sciences 105:23, 8073-8078
CrossRef136
Jeffrey J Swigris, Kevin K Brown. (2008) Evaluation of bosentan for idiopathic pulmonary fibrosis. Expert Review of Respiratory Medicine 2:3, 315-321
CrossRef137
R. T. Calado, N. S. Young. (2008) Telomere maintenance and human bone marrow failure. Blood 111:9, 4446-4455
CrossRef138
Inderjeet Dokal, Tom Vulliamy. (2008) Inherited aplastic anaemias/bone marrow failure syndromes. Blood Reviews 22:3, 141-153
CrossRef139
Calvin B. Harley. (2008) Telomerase and cancer therapeutics. Nature Reviews Cancer 8:3, 167-179
CrossRef140
P. M. Lansdorp. (2008) Telomeres, stem cells, and hematology. Blood 111:4, 1759-1766
CrossRef141
M Kirwan, I Dokal. (2008) Dyskeratosis congenita: a genetic disorder of many faces. Clinical Genetics 73:2, 103-112
CrossRef142
Benjamin D. Bringardner, Christopher P. Baran, Timothy D. Eubank, Clay. B. Marsh. (2008) The Role of Inflammation in the Pathogenesis of Idiopathic Pulmonary Fibrosis. Antioxidants & Redox Signaling 10:2, 287-302
CrossRef143
Robert H. Vonderheide. (2008) Prospects and challenges of building a cancer vaccine targeting telomerase. Biochimie 90:1, 173-180
CrossRef144
T.J. Vulliamy, I. Dokal. (2008) Dyskeratosis congenita: The diverse clinical presentation of mutations in the telomerase complex. Biochimie 90:1, 122-130
CrossRef145
Zhenyu Ju, Lenhard Rudolph. (2008) Telomere dysfunction and stem cell ageing. Biochimie 90:1, 24-32
CrossRef146
J. D. Podlevsky, C. J. Bley, R. V. Omana, X. Qi, J. J.-L. Chen. (2007) The Telomerase Database. Nucleic Acids Research 36:Database, D339-D343
CrossRef147
A. Marrone, A. Walne, H. Tamary, Y. Masunari, M. Kirwan, R. Beswick, T. Vulliamy, I. Dokal. (2007) Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood 110:13, 4198-4205
CrossRef148
J. Sibilia. (2007) Quoi de neuf en médecine en 2007 ?. Annales de Dermatologie et de Vénéréologie 134, 8S24-8S35
CrossRef149
Maria A Blasco. (2007) Telomere length, stem cells and aging. Nature Chemical Biology 3:10, 640-649
CrossRef150
H. Jiang, Z. Ju, K. L. Rudolph. (2007) Telomere shortening and ageing. Zeitschrift für Gerontologie und Geriatrie 40:5, 314-324
CrossRef151
Norman E. Sharpless, Ronald A. DePinho. (2007) How stem cells age and why this makes us grow old. Nature Reviews Molecular Cell Biology 8:9, 703-713
CrossRef152
Sonja Schaetzlein, N.R. Kodandaramireddy, Zhenyu Ju, Andre Lechel, Anna Stepczynska, Dana R. Lilli, Alan B. Clark, Cornelia Rudolph, Florian Kuhnel, Kaichun Wei, Brigitte Schlegelberger, Peter Schirmacher, Thomas A. Kunkel, Roger A. Greenberg, Winfried Edelmann, K. Lenhard Rudolph. (2007) Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice. Cell 130:5, 863-877
CrossRef153
Toren Finkel, Manuel Serrano, Maria A. Blasco. (2007) The common biology of cancer and ageing. Nature 448:7155, 767-774
CrossRef154
Verma, Subodh, Slutsky, Arthur S., . (2007) Idiopathic Pulmonary Fibrosis — New Insights. New England Journal of Medicine 356:13, 1370-1372
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