The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index; none of the 31 sources its claims cite is checked for support yet.
Adult-onset pulmonary fibrosis caused by mutations in telomerase
Open accessAbstract
Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology. Some individuals with IPF have a familial disorder that segregates as a dominant trait with incomplete penetrance. Here we used linkage to map the disease gene in two families to chromosome 5. Sequencing a candidate gene within the interval, TERT , revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families. TERT encodes telomerase reverse transcriptase, which together with the RNA component of telomerase ( TERC ), is required to maintain telomere integrity. Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT . A heterozygous mutation in TERC also was found in one family. Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations. Thus, mutations in TERT or TERC that result in telomere shortening over time confer a dramatic increase in susceptibility to adult-onset IPF.
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Written from the paper’s full text.
TL;DR
Mutations in *TERT* or *TERC* that cause telomere shortening confer susceptibility to adult-onset idiopathic pulmonary fibrosis (IPF). The study links telomerase dysfunction to familial and sporadic IPF, with incomplete penetrance and possible smoking exacerbation.
Key findings
- Linkage in two large families mapped disease to chromosome 5p15 with a maximal LOD score of 2.8; sequencing the candidate gene *TERT* found a missense mutation (R865H) and a frameshift mutation (V747fsX766) that cosegregated with pulmonary disease.
- In 44 additional unrelated familial interstitial lung disease probands and 44 sporadic cases, five other *TERT* mutations were found (total: two frameshift deletions and five missense mutations), plus one heterozygous *TERC* mutation (r.37a>g); none of the seven *TERT* mutations were found in 94 ethnically matched controls, 200 patients with aplastic anemia, or a multiethnic panel of 528 controls.
- Heterozygous carriers of *TERT* or *TERC* mutations had shorter telomeres than age-matched family members without the mutations; in vitro TRAP assays showed frameshift mutants had little detectable telomerase activity, missense and *TERC* mutants ranged from zero to 100% of wild-type activity, and mixing V747fs with wild-type *TERT* suggested haploinsufficiency.
- Among mutation carriers, smokers died at an average age of 58 years (n = 13) versus 68 years for nonsmokers (n = 7); all affected individuals developed pulmonary fibrosis in adulthood with no history of pediatric lung disease.
Methods
- Clinical sample: 46 families with two or more cases of idiopathic interstitial lung disease (34 of 46 families had individuals with IPF) and 44 sporadic interstitial lung disease cases (31 with IPF); genomic DNA was isolated from leukocytes, and for four individuals from formalin-fixed paraffin-embedded archival samples.
- Linkage analysis: whole-genome SNP genotyping with the Illumina Linkage IVb panel of >6,000 polymorphic SNPs; MERLIN was used for multipoint model-free and model-based linkage analysis, with the highest peak on chromosome 5p15.
- Mutation and functional analysis: *TERT* exons and splice sites and 451 bp encoding *TERC* were sequenced; telomerase activity was measured by the TRAP assay using in vitro coexpressed recombinant protein and RNA; telomere length was assessed by terminal restriction fragment (TRF) Southern blot analysis of leukocyte DNA.
Limitations
- The paper does not include a formal limitations section; it states that pulmonary fibrosis appears to be a human-specific manifestation of telomerase deficiency and that it is not yet reported whether aged telomerase-deficient mice develop similar lung pathology.
- The paper notes incomplete penetrance: some family members who inherited a *TERT* mutation had no evidence of pulmonary disease, and environmental influences such as cigarette smoking may affect the phenotype.
- Evident from the text: linkage mapping relied on two families, mutation screening focused on the candidate genes *TERT* and *TERC*, and in vitro TRAP activity did not always track telomere shortening because some mutations caused telomere shortening without a detectable decrease in telomerase activity.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sequencing a candidate gene within the interval, TERT, revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families.”
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In the paper
“A heterozygous mutation in TERC also was found in one family.”
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In the paper
“Here we used linkage to map the disease gene in two families to chromosome 5.”
- Also stated in: § Results · plain
“Both families displayed linkage to chromosome 5p15 with a maximal logarithm of odds (LOD) score of 2.8.”
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT.”
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In the paper
“Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations.”
- Also stated in: § Results · plain
“When compared with normal family members of similar age, the mean telomere length was significantly shorter for those individuals who were heterozygous for a mutation in TERT or TERC (Fig. 5 A and B).”
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In the paper
“Thus, a total of two frameshift deletions and five missense mutations in TERT were identified in patients with pulmonary fibrosis (Fig. 3).”
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In the paper
“When telomere lengths were analyzed within families, the family members with clinical disease tended to have shorter TRFs than the asymptomatic carriers.”
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In the paper
“Mixing different amounts of the V747fs TERT construct with the wild-type TERT construct did not affect the activity of the wild-type protein, suggesting a mechanism of haploinsufficiency (Fig. 4D).”
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In the paper
“The proband of family F11 was heterozygous for a transition mutation (CGT → CAT) in codon 865 that is predicted to change a highly conserved arginine to a histidine.”
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In the paper
“The five missense mutations in TERT (Fig. 4 B and C) and the mutation in TERC (Fig. 4 A and C) produced levels of telomerase activity that ranged from zero to 100% of wild-type activity.”
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In the paper
“Four additional sequence variations, including three missense mutations and one 177-bp deletion, were found (Fig. 3).”
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In the paper
“None of the seven mutations were found in 94 locally collected, ethnically matched individuals, nor were they detected in 200 patients with aplastic anemia or a multiethnic panel of 528 individuals sequenced as controls (9).”
What the sources say
- Not checked yetcites [9] Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. N Engl J Med. 2005;352:1413–1424. doi: 10.1056/NEJMoa042980. [DOI] [PubMed] [Google Scholar] source
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In the paper
“All developed pulmonary fibrosis during their adult years with no history of pediatric lung disease, in contrast with kindreds associated with surfactant protein C mutations (18, 19).”
What the sources say
- Not checked yetcites [18] Thomas AQ, Lane K, Phillips J, III, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, et al. Am J Respir Crit Care Med. 2002;165:1322–1328. doi: 10.1164/rccm.200112-123OC. [DOI] [PubMed] [Google Scholar] source
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In the paper
“None had aplastic anemia but several exhibited a mild to moderate anemia and one individual developed neutropenia after lung transplantation.”
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In the paper
“One additional missense mutation was identified involving the same arginine at codon 865 found to be mutated in family F11.”
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In the paper
“Another individual with a TERT mutation in this family had very short TRFs but did not have IPF. This individual had cirrhosis of unknown etiology.”
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In the paper
“The proband of family F31 was heterozygous for a deletion of thymidine at position 2240 in the cDNA, which creates a frameshift in the reading frame and is predicted to result in a truncated protein missing half of the reverse-transcriptase domain and the entire C-terminal region.”
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In the paper
“As expected, the mutation (V747fs, Fig. 4 A and C) missing half the reverse transcriptase domain and the mutation (E1116fs; Fig. 4C) missing the C-terminal E-IV domain had very little detectable telomerase activity.”
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In the paper
“This change was not detected in 94 ethnically matched controls but was identified previously in a person with severe aplastic anemia who was a compound heterozygote for variants in TERC (12).”
What the sources say
- Not checked yetcites [12] Ly H, Schertzer M, Jastaniah W, Davis J, Yong SL, Ouyang Q, Blackburn EH, Parslow TG, Lansdorp PM. Blood. 2005;106:1246–1252. doi: 10.1182/blood-2005-01-0247. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper
“A number of individuals had evidence of axial osteoporosis; in many cases, this diagnosis preceded or was determined in the absence of lung disease.”
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In the paper
“For both families, some family members with TERT mutations exhibited other clinical features of DKC (7), such as osteoporosis/osteopenia, anemia and cancer (Table 1), but none of the affected individuals had the mucocutaneous lesions typical of DKC.”
What the sources say
- Not checked yetcites [7] Dokal I. Br J Haematol. 2000;110:768–779. doi: 10.1046/j.1365-2141.2000.02109.x. [DOI] [PubMed] [Google Scholar] source
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In the paper
“The individuals with TERT or TERC mutations have none of the physical manifestations of DKC and were all ascertained by the lung fibrosis phenotype, distinguishing them from previously described patients with mutations in these genes (6, 9, 10, 17).”
What the sources say
- Not checked yetcites [6] Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Proc Natl Acad Sci USA. 2005;102:15960–15964. doi: 10.1073/pnas.0508124102. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper
“One proband of a Caucasian family (F61) was heterozygous for an adenosine and guanine at position 37.”
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In the paper
“Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology.”
- Also stated in: § Abstract · plain
“IPF is distinguished from the other interstitial lung diseases by its unknown etiology, by characteristic abnormalities on pulmonary function tests and radiographs, and by biopsy findings, which include evidence of injury occurring over time with foci of replicating fibroblasts at the interface between normal and scarred lung tissue (3).”
What the sources say
- Not checked yetcites [3] American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med. 2002;165:277–304. doi: 10.1164/ajrccm.165.2.ats01. [DOI] [PubMed] [Google Scholar] source
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In the paper
“Among the genes we evaluated was TERT, which was considered a candidate because a mutation in this gene was recently reported to cause autosomal dominant dyskeratosis congenita (DKC), a disorder in which 20% of affected individuals develop pulmonary fibrosis (6, 7).”
What the sources say
- Not checked yetcites [6] Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Proc Natl Acad Sci USA. 2005;102:15960–15964. doi: 10.1073/pnas.0508124102. [DOI] [PMC free article] [PubMed] [Google Scholar] source
- Not checked yetcites [7] Dokal I. Br J Haematol. 2000;110:768–779. doi: 10.1046/j.1365-2141.2000.02109.x. [DOI] [PubMed] [Google Scholar] source
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In the paper
“The clinical presentation of familial IPF is indistinguishable from sporadic IPF except that the age of onset tends to be earlier (55 years vs. 67 years) (4, 5).”
What the sources say
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In the paper
“All sequences were determined in both directions, the mutations were confirmed by three separate PCR amplification products, and both genes were sequenced in their entirety for all subjects.”
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In the paper
“Telomere length is also influenced by oxidative damage (24) that, in part, may explain why lung disease is the predominant phenotype and why smoking may exacerbate this disease.”
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In the paper
“The pathologic features of IPF suggest that the lung injury is focal, affecting scattered portions of the lung parenchyma and recurring over many years (21).”
What the sources say
- Not checked yetcites [21] Katzenstein AL, Myers JL. Am J Respir Crit Care Med. 1998;157:1301–1315. doi: 10.1164/ajrccm.157.4.9707039. [DOI] [PubMed] [Google Scholar] source
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In the paper
“Repeat experiments showed the same relative trend of TRAP activities.”
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In the paper
“Multiple different mutations in TERC have been described for patients with DKC (10).”
What the sources say
- Not checked yetcites [10] Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I. Nature. 2001;413:432–435. doi: 10.1038/35096585. [DOI] [PubMed] [Google Scholar] source
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In the paper
“Pulmonary fibrosis appears to be a human-specific manifestation of telomerase deficiency.”
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In the paper
“Call rates varied from 99.7–100% for Autopure-purified DNA and between 72–98% for whole-genome-amplified DNA extracted from archival samples.”
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In the paper
“Telomerase may be a marker for identifying resident stem cells that promote regeneration and prevent premature aging of the lung.”
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In the paper
“Smoking causes telomere shortening in a dose-dependent manner (22) and is associated with familial interstitial pneumonia (23).”
What the sources say
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In the paper
“Interestingly, a recent trial with high doses of the antioxidant acetylcysteine appeared to attenuate the progression of IPF (25).”
What the sources say
- Not checked yetcites [25] Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, MacNee W, Thomeer M, Wallaert B, Laurent F, et al. N Engl J Med. 2005;353:2229–2242. doi: 10.1056/NEJMoa042976. [DOI] [PubMed] [Google Scholar] source
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In the paper
“This report provides previously undescribed molecular insight into the pathogenesis of IPF and expands the scope of diseases caused by mutations in telomerase.”
Tests✓ Asserted: passes? Checkable: unclear✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Telomere length is influenced by many different factors, including age (13, 14) and the number of generations the mutation is transmitted (6, 15).”
What the sources say
- Not checked yetcites [13] Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC. Nature. 1990;346:866–868. doi: 10.1038/346866a0. [DOI] [PubMed] [Google Scholar] source
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In the paper
“This study was approved by the University of Texas Southwestern Institutional Review Board. Written informed consent was obtained from all participants.”
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In the paper
“Such a pattern of injury could explain why the pulmonary phenotype is incompletely penetrant and may be influenced not only by the nature of the mutations but also by environmental influences, such as cigarette smoking.”
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The paper relies on this without support.
TERT encodes telomerase reverse transcriptase, which together with TERC is required to maintain telomere integrity.
“TERT encodes telomerase reverse transcriptase, which together with the RNA component of telomerase (TERC), is required to maintain telomere integrity.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“The fact that AAV9-TERT treatment of old mice efficiently reactivated telomerase in the lungs offers a therapeutic opportunity for some cases of human pulmonary fibrosis associated with presence of short telomeres owing to telomerase mutations (Armanios et al, 2007; Tsakiri et al, 2007).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Tsakiri et al, 2007
In the citing paper
“The frequency of these mutations is highest in individuals with the progressive disorder IPF, which accounts for 8–15% of familial and 1–3% of sporadic cases54,56,68,69.”
From The telomere syndromes (2012) · cites this paper as [68]
In the citing paper
“By contrast, telomere shortening is accelerated in several human premature ageing syndromes, and patients with dyskeratosis congenita and aplastic anaemia show decreased telomerase activity and shortened telomeres owing to mutations in the TERC and TERT telomerase genes.”
From The common biology of cancer and ageing (2007) · cites this paper as [63]
In the citing paper
“patients who have inherited or acquired genetic defects that limit telomere maintenance seem to be at substantially increased risk of a range of conditions including aplastic anaemia 61 , idiopathic pulmonary fibrosis 62, 63 and the rarer dyskeratosis congenita syndrome”
From The common biology of cancer and ageing (2007) · cites this paper as [63]
Citations
Cites
Telomeres shorten during ageing of human fibroblasts
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Oxidative stress shortens telomeres
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Telomerase Catalytic Subunit Homologs from Fission Yeast and Human
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Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice
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Incidence and Prevalence of Idiopathic Pulmonary Fibrosis
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Self-citationIdiopathic Pulmonary Fibrosis: Clinical Relevance of Pathologic Classification
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Helling, B. A., & Yang, I. V. (2015) · Current Opinion in Pulmonary Medicine · doi:10.1097/mcp.0000000000000191 · Cited by 66
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“(TERT) and telomerase RNA component (TERC) [43,44].”
BackgroundCooper, W. A., Mahar, A. M., Myers, J. L., Grainge, C., Corte, T. J., Williamson, J., Vallely, M. P., Lai, S., Mulyadi, E., Torzillo, P. J., et al. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202009-3688oc · Cited by 65
Self-citationTargeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option
Korfei, M., Mahavadi, P., & Guenther, A. (2022) · Cells · doi:10.3390/cells11101626 · Cited by 66
“The deacetylation of HSP90 by HDAC6 has been associated with the stabilisation of several HSP90 oncogenic client proteins, such as AKT, hypoxia-inducible factor 1-alpha (HIF1-α), surviving and TERT, and is thus linked to carcinogenesis [186,188].”
BackgroundSiegl-Cachedenier, I., Flores, I., Klatt, P., & Blasco, M. A. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704141 · Cited by 64
“…Vulliamy et al., 2001, 2004; Mason et al., 2005), aplastic anemia (Marrone et al., 2004; Yamaguchi et al., 2005), and idiopathic pulmonary fi brosis (Armanios et al., 2007; Tsakiri et al., 2007) leads to accelerated telomere shortening, premature loss of tissue regeneration, and premature death.”
Triallelic and epigenetic-like inheritance in human disorders of telomerase
Collopy, L. C., Walne, A. J., Cardoso, S. R., de la Fuente, J., Mohamed, M., Toriello, H. V., Tamary, H., Ling, A. J. Y. V., Lloyd, T., Kassam, R., et al. (2015) · Blood · doi:10.1182/blood-2015-03-633388 · Cited by 66
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“The telomerase-related genes (TERT and TERC) [8,9], surfactant proteins C (SPC) and A2 (SPA2) have been identified to be associated with familial IPF [8,10].”
BackgroundTelomere Biology and Telomere Diseases: Implications for Practice and Research
Young, N. S. (2010) · Hematology · doi:10.1182/asheducation-2010.1.30 · Cited by 66
Cutting, C. C., Bowman, W. S., Đao, N. H., Pugashetti, J. V., Garcia, C. K., Oldham, J. M., & Newton, C. A. (2021) · CHEST Journal · doi:10.1016/j.chest.2021.01.026 · Cited by 65
Self-citationJónsdóttir, H. R., Arason, A. J., Pálsson, R., Franzdóttir, S. R., Guðbjartsson, T., Ísaksson, H. J., Gudmundsson, G., Guðjónsson, Þ., & Magnússon, M. K. (2015) · Laboratory Investigation · doi:10.1038/labinvest.2015.114 · Cited by 65
Lawson, W. E., Loyd, J. E., & Degryse, A. L. (2011) · The American Journal of the Medical Sciences · doi:10.1097/maj.0b013e31821a9d7a · Cited by 65
Endogenous Lung Regeneration: Potential and Limitations
Rock, J. R., & Königshoff, M. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201207-1151pp · Cited by 64
New Insights into the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis
Ding, Q., Luckhardt, T., Hecker, L., Zhou, Y., Liu, G., Antony, V. B., deAndrade, J. A., & Thannickal, V. J. (2011) · Drugs · doi:10.2165/11591490-000000000-00000 · Cited by 62
“Recent studies of familial and sporadic cases of IPF have been associated with telomere shortening,([70-72]) suggesting that IPF may represent a degenerative disease process associated with advancing age.”
BackgroundTelomeres and Telomerase in the Development of Liver Cancer
der Stroth, L. I., Tharehalli, U., Güneş, Ç., & Lechel, A. (2020) · Cancers · doi:10.3390/cancers12082048 · Cited by 66
Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging
Piñeiro-Hermida, S., Autilio, C., Martínez, P., Bosch, F., Pérez-Gil, J., & Blasco, M. A. (2020) · Journal of Cell Biology · doi:10.1083/jcb.202002120 · Cited by 60
Courtwright, A., Lamattina, A. M., Takahashi, M., Trindade, A. J., Hunninghake, G. M., Rosas, I. O., Agarwal, S., Raby, B. A., Goldberg, H. J., & El‐Chemaly, S. (2020) · ERJ Open Research · doi:10.1183/23120541.00003-2020 · Cited by 62
Idiopathic Pulmonary Fibrosis: An Altered Fibroblast Proliferation Linked to Cancer Biology
Vancheri, C. (2012) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201203-025aw · Cited by 61
Telomere rejuvenation during nuclear reprogramming
Marión, R. M., & Blasco, M. A. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.01.005 · Cited by 62
Pathogenic TERT promoter variants in telomere diseases
Gutierrez‐Rodrigues, F., Donaires, F. S., Pinto, A., Vicente, A., Dillon, L. W., Clé, D. V., Santana, B. A., Pirooznia, M., Ibanez, M. D. P. F., Townsley, D. M., et al. (2018) · Genetics in Medicine · doi:10.1038/s41436-018-0385-x · Cited by 61
Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis
Ptasinski, V., Stegmayr, J., Belvisi, M. G., Wagner, D. E., & Murray, L. A. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0476tr · Cited by 60
“These include mutations in hTERT (human telomerase), the enzyme responsible for maintaining the length of the telomeres, which cause accelerated shortening of the telomeres (64, 65).”
BackgroundThe Genetic and Environmental Causes of Pulmonary Fibrosis
Macneal, K., & Schwartz, D. A. (2012) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201112-055aw · Cited by 59
Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease
Boyraz, B., Moon, D. H., Segal, M., Muosieyiri, M. Z., Aykanat, A., Tai, A., Cahan, P., & Agarwal, S. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87547 · Cited by 60
Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis
Zhang, D., Povysil, G., Kobeissy, P. H., Li, Q., Wang, B., Amelotte, M., Jaouadi, H., Newton, C. A., Maher, T. M., Molyneaux, P. L., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202110-2439oc · Cited by 56
Self-citationThe role of telomere trimming in normal telomere length dynamics
Pickett, H. A., & Reddel, R. R. (2012) · Cell Cycle · doi:10.4161/cc.19632 · Cited by 61
Idiopathic Pulmonary Fibrosis is a Genetic Disease Involving Mucus and the Peripheral Airways
Schwartz, D. A. (2018) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201802-144aw · Cited by 61
Idiopathische Lungenfibrose – Epidemiologie, Ursachen und klinischer Verlauf
Schäfer, S. C., Funke-Chambour, M., & Berezowska, S. (2020) · Der Pathologe · doi:10.1007/s00292-019-00747-x · Cited by 58
The Role of Genetic Testing in Pulmonary Fibrosis
Newton, C. A., Oldham, J. M., Applegate, C. D., Carmichael, N. E., Powell, K. P., Dilling, D. F., Schmidt, S. L., Scholand, M. B., Armanios, M. Y., Garcia, C. K., et al. (2022) · CHEST Journal · doi:10.1016/j.chest.2022.03.023 · Cited by 62
Self-citationStanley, S. E., Merck, S. J., & Armanios, M. Y. (2016) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201609-718aw · Cited by 58
Zhang, D., & Newton, C. A. (2021) · CHEST Journal · doi:10.1016/j.chest.2021.06.037 · Cited by 61
Telomeres and Telomerase in Lung Cancer
Fernandez‐Garcia, I., Ortíz-de-Solórzano, C., & Montuenga, L. M. (2008) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181886713 · Cited by 55
Liu, T., Santos, F. G. D. L., Zhao, Y., Wu, Z. B., Rinke, A. E., Kim, K. K., & Phan, S. H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006615 · Cited by 57
“Mutant TERT, TR, and/or shortened telomeres in peripheral blood leukocytes are amply documented as risk factors for idiopathic pulmonary fibrosis (IPF) (3, 4, 20, 21).”
BackgroundGenetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis
Michalski, J. E., & Schwartz, D. A. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s280958 · Cited by 61
Advances in quantum dot-based biosensors for DNA-modifying enzymes assay
Zhang, Q., Zhang, X., Ma, F., & Zhang, C. (2022) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2022.214674 · Cited by 55
Hambly, N., Shimbori, C., & Kolb, M. R. J. (2015) · Respirology · doi:10.1111/resp.12569 · Cited by 60
Telomere and telomerase in chronic liver disease and hepatocarcinoma
Carulli, L. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i20.6287 · Cited by 56
Workshop on Idiopathic Pulmonary Fibrosis in Older Adults
Castriotta, R. J., Eldadah, B. A., Foster, W. M., Halter, J. B., Hazzard, W. R., Kiley, J. P., King, T. E., Horne, F. M., Nayfield, S., Reynolds, H. Y., et al. (2010) · CHEST Journal · doi:10.1378/chest.09-3006 · Cited by 57
STAT3: A Central Mediator of Pulmonary Fibrosis?
Prêle, C. M., Yao, E., O’Donoghue, R. J. J., Mutsaers, S. E., & Knight, D. A. (2012) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201201-007aw · Cited by 54
Telomerase deficiency does not alter bleomycin-induced fibrosis in mice
Degryse, A. L., Xu, X. C., Newman, J., Mitchell, D. B., Tanjore, H., Polosukhin, V. V., Jones, B. R., McMahon, F. B., Gleaves, L. A., Phillips, J. A., et al. (2012) · Experimental Lung Research · doi:10.3109/01902148.2012.658148 · Cited by 57
“With these mutations, decreased telomerase activity is noted and telomere shortening is severe with many mutation carriers having peripheral blood leukocyte telomere lengths less than 10% (and some less than 1%) of age-matched controls [15, 16].”
Profibrotic role of WNT10A via TGF-β signaling in idiopathic pulmonary fibrosis
Oda, K., Yatera, K., Izumi, H., Ishimoto, H., Yamada, S., Nakao, H., Hanaka, T., Ogoshi, T., Noguchi, S., & Mukae, H. (2016) · Respiratory Research · doi:10.1186/s12931-016-0357-0 · Cited by 53
“Previous studies have reported several genetic factors associated with mortality in IPF, such as erythrocyte complement receptor 1 [39], telomerase reverse transcriptase [40] and the MUC 5B gene [41].”
BackgroundPredictive factors and prognostic effect of telomere shortening in pulmonary fibrosis
Planas‐Cerezales, L., Arias‐Salgado, E. G., Buendía-Roldán, I., Montes‐Worboys, A., Esquinas, C., Vicens‐Zygmunt, V., Hernaiz, P. L., Sanuy, R. L., Leiro‐Fernández, V., Balcells, E., et al. (2018) · Respirology · doi:10.1111/resp.13423 · Cited by 55
Tirelli, C., Pesenti, C., Miozzo, M. R., Mondoni, M., Fontana, L., & Centanni, S. (2022) · Diagnostics · doi:10.3390/diagnostics12123107 · Cited by 55
“It has been hypothesized [21,27] that as many as 25% of sporadic IPF and 37% of FPF might have shorter telomeres.”
BackgroundHuman telomerase expression regulation
Machnik, M., Wojtyla, A., & Rubiś, B. (2011) · Biochemistry and Cell Biology · doi:10.1139/o11-037 · Cited by 56
“…polymorphisms identified in TERT resulted in susceptibility to dyskeratosis congenita and haploinsufficiency (Armanios et al. 2005, 2007) or adult-onset idiopathic pulmonary fibrosis (IPF) (Tsakiri et al. 2007; Alder et al. 2008) and coronary artery disease (Matsubara et al. 2006).”
BackgroundFibrosis: Lessons from OMICS analyses of the human lung
Yu, G., Ibarra, G. H., & Kaminski, N. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.03.014 · Cited by 52
Combined pulmonary fibrosis and emphysema
Papiris, S. A., Triantafillidou, C., Manali, E. D., Kolilekas, L., Baou, K., Kagouridis, K., & Bouros, D. E. (2013) · Expert Review of Respiratory Medicine · doi:10.1586/ers.12.80 · Cited by 52
Genetic Interstitial Lung Disease
Devine, M., & Garcia, C. K. (2011) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2011.11.001 · Cited by 55
Self-citationFeurstein, S. K., Adegunsoye, A., Mojsilovic, D., Vij, R., DePersia, A., Rajagopal, P. S., Osman, A. E. G., Collins, R. H., Kim, R. H., Gore, S. D., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020001721 · Cited by 53
Okuda, R., Aoshiba, K., Matsushima, H., Ogura, T., Okudela, K., & Ohashi, K. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.02.11 · Cited by 49
“For IPF, the hypofunct ion of telomerase reverse transcriptase has been reported in 15% of patients with familial interstitial pneumonia and 3% of patients with sporadic IPF (7,34).”
BackgroundBorie, R., Kannengiesser, C., Nathan, N., Tabèze, L., Pradère, P., & Crestani, B. (2014) · Revue des Maladies Respiratoires · doi:10.1016/j.rmr.2014.07.017 · Cited by 54
Beach, T. A., Johnston, C. J., Groves, A. M., Williams, J. P., & Finkelstein, J. N. (2017) · Experimental Lung Research · doi:10.1080/01902148.2017.1318975 · Cited by 50
“Plasmin dissolves fibrin in blood clots and is an important protease in many other cellular processes, particularly extracellular matrix disassembly, while angiostatin inhibits angiogenesis Tert Telomerase reverse transcriptase Tert mutations have been associated with interstitial lung disease [90] Shortened telomeres…”
BackgroundLee, J. S., La, J. L., Aziz, S., Dobrinskikh, E., Brownell, R., Jones, K. D., Achtar‐Zadeh, N., Green, G., Elicker, B. M., Golden, J. A., et al. (2021) · Histopathology · doi:10.1111/his.14334 · Cited by 52
The clinical and functional effects of TERT variants in myelodysplastic syndrome
Reilly, C. R., Myllymäki, M., Redd, R. A., Padmanaban, S., Karunakaran, D., Tesmer, V. M., Tsai, F. D., Gibson, C. J., Rana, H. Q., Zhong, L., et al. (2021) · Blood · doi:10.1182/blood.2021011075 · Cited by 51
Translational research in pulmonary fibrosis
Mathai, S. K., & Schwartz, D. A. (2019) · Translational research · doi:10.1016/j.trsl.2019.02.001 · Cited by 50
Zhang, D., Newton, C. A., Wang, B., Povysil, G., Noth, I., Martínez, F. J., Raghu, G., Goldstein, D. B., & Garcia, C. K. (2022) · European Respiratory Journal · doi:10.1183/13993003.00577-2022 · Cited by 48
Self-citationGeorge, G., Rosas, I. O., Cui, Y., McKane, C. K., Hunninghake, G. M., Camp, P. C., Raby, B. A., Goldberg, H. J., & El‐Chemaly, S. (2014) · CHEST Journal · doi:10.1378/chest.14-0631 · Cited by 50
Epigenomics of Idiopathic Pulmonary Fibrosis
Yang, I. V. (2012) · Epigenomics · doi:10.2217/epi.12.10 · Cited by 49
Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita
Agarwal, S. (2018) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2018.04.003 · Cited by 51
Smoking-associated interstitial lung disease: update and review
Dawod, Y., Cook, N. E., Graham, W. B., MADHANI-LOVELY, F. K., & Thao, C. (2020) · Expert Review of Respiratory Medicine · doi:10.1080/17476348.2020.1766971 · Cited by 53
Senescence in Pulmonary Fibrosis: Between Aging and Exposure
Venosa, A. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.606462 · Cited by 51
miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways
Ge, L., Habiel, D. M., Hansbro, P. M., Kim, R., Gharib, S. A., Edelman, J. D., Königshoff, M., Parimon, T., Brauer, R., Huang, Y., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.90301 · Cited by 51
Ota, C., Ng-Blichfeldt, J.-P., Korfei, M., Alsafadi, H. N., Lehmann, M., Skrońska-Wąsek, W., Santis, M. M. D., Günther, A., Wagner, D. E., & Königshoff, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-31214-x · Cited by 49
Telomere Dysfunction in Idiopathic Pulmonary Fibrosis
Zhang, K., Xu, L., & Cong, Y. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.739810 · Cited by 51
“A breakthrough discovery using linkage analysis identified TERT mutations in two IPF families (23).”
BackgroundMolecular mechanisms of ageing and related diseases
Liu, J. (2014) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12247 · Cited by 50
Telomerase RNA processing: Implications for human health and disease
Nagpal, N., & Agarwal, S. (2020) · Stem Cells · doi:10.1002/stem.3270 · Cited by 47
Molecular pathways and role of epigenetics in the idiopathic pulmonary fibrosis
Velagacherla, V., Mehta, C. H., Nayak, Y., & Nayak, U. Y. (2022) · Life Sciences · doi:10.1016/j.lfs.2021.120283 · Cited by 48
Tárkányi, I., & Aradi, J. (2007) · Biochimie · doi:10.1016/j.biochi.2007.09.002 · Cited by 48
Interstitial Lung Disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases
Rosas, I. O., Dellaripa, P. F., Lederer, D. J., Khanna, D., Young, L. R., & Martínez, F. J. (2014) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201312-429ld · Cited by 46
Personalized medicine in idiopathic pulmonary fibrosis
Spagnolo, P., Τzouvelekis, Α., & Maher, T. M. (2015) · Current Opinion in Pulmonary Medicine · doi:10.1097/mcp.0000000000000187 · Cited by 48
Tsang, A. R., Wyatt, H. D. M., Ting, N. S. Y., & Beattie, T. L. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00810.x · Cited by 48
“Recently, mutations in the hTERT and hTR genes have been identified in a subset of patients with idiopathic pulmonary fibrosis (IPF) (Armanios et al., 2007; Tsakiri et al., 2007).”
BackgroundInfluentialBorie, R., Cardwell, J., Konigsberg, I. R., Moore, C. M., Zhang, W. E., Sasse, S. K., Gally, F., Dobrinskikh, E., Walts, A. D., Powers, J., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202110-2308oc · Cited by 45
ATM-like kinases and regulation of telomerase: lessons from yeast and mammals
Sabourin, M., & Zakian, V. A. (2008) · Trends in Cell Biology · doi:10.1016/j.tcb.2008.04.004 · Cited by 45
Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis
Hwang, J. A., Kim, D., Chun, S., Bae, S., Song, J. S., Kim, M. Y., Koo, H. J., Song, J. W., Kim, W. S., Lee, J. C., et al. (2017) · The Journal of Pathology · doi:10.1002/path.4978 · Cited by 46
“Mutations in TERT are known to decrease the stability of the telomerase complex or the activation of the telomerase, thus increasing the susceptibility to adult-onset IPF [50,51], and CDKN1A, encoding the cell cycle”
BackgroundArish, N., Petukhov, D., & Wallach‐Dayan, S. B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20122996 · Cited by 46
“The mutations are not only in the familial IPF; one mutation in Tert was found in a subject with the sporadic form of the disease who had no family history of IPF [50].”
BackgroundAutophagy in pulmonary fibrosis: friend or foe?
Hill, C. N., & Wang, Y. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.09.008 · Cited by 46
Ellingsen, E. B., Aamdal, E., Guren, T. K., Lilleby, W. A., Brunsvig, P. F., Mangsbo, S. M., Aamdal, S., Hovig, E. J., Mensali, N., Gaudernack, G., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004345 · Cited by 43
Newton, D. A., Lottes, R. G., Ryan, R. M., Spyropoulos, D. D., & Baatz, J. E. (2021) · Respiratory Research · doi:10.1186/s12931-021-01866-x · Cited by 46
KLF4 regulates TERT expression in alveolar epithelial cells in pulmonary fibrosis
Wang, H., Xu, H., Lyu, W., Xu, Q., Fan, S., Chen, H., Wang, D., Chen, J., & Dai, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04886-7 · Cited by 46
The Genetic Landscape of Familial Pulmonary Fibrosis
Liu, Q., Zhou, Y., Cogan, J. D., Mitchell, D. B., Sheng, Q., Zhao, S., Bai, Y., Ciombor, K. K., Sabusap, C. M. P., Malabanan, M. M., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202204-0781oc · Cited by 48
Natural History of Pulmonary Fibrosis in Two Subjects With the Same Telomerase Mutation
El‐Chemaly, S., Ziegler, S. G., Calado, R. T., Wilson, K. A., Wu, H. P., Haughey, M., Peterson, N. R., Young, N. S., Gahl, W. A., Moss, J., et al. (2010) · CHEST Journal · doi:10.1378/chest.10-2048 · Cited by 47
Fibrocytes Regulate Wilms Tumor 1–Positive Cell Accumulation in Severe Fibrotic Lung Disease
Sontake, V., Shanmukhappa, S. K., DiPasquale, B. A., Reddy, G. B., Medvedovic, M., Hardie, W. D., White, E. S., & Madala, S. K. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500963 · Cited by 44
“Similarly, TERT mutations are the most common genetic defect found in familial pulmonary fibrosis (65, 66).”
BackgroundGaysinskaya, V. A., Stanley, S. E., Adam, S. S., & Armanios, M. Y. (2020) · CHEST Journal · doi:10.1016/j.chest.2020.07.025 · Cited by 43
Autoantibodies targeting telomere-associated proteins in systemic sclerosis
Adler, B. L., Boin, F., Wolters, P. J., Bingham, C. O., Shah, A. A., Greider, C. W., Casciola-Rosen, L. A., & Rosen, A. (2021) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2020-218918 · Cited by 45
Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases
Ruíz, A., Flores‐González, J., Buendía-Roldán, I., & Chávez‐Galán, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010425 · Cited by 46
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“Another example where telomerase mutations might play a causal role is pulmonary fibrosis (53).”
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“2 Encodes a telomerase component (the RNA template) Abnormal alveolar epithelial cell turnover and repair after injury Susceptibility to familial idiopathic interstitial pneumonia [95,96]”
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“Recently, Tsakiri and colleagues [12] have demonstrated that there is a relationship between adult-onset pulmonary fibrosis and mutations in telomerase.”
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“Patients with familial IIPs and mutations in TERT and TERC were the first to be shown to have short peripheral blood TL [18,35].”
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“Additional human subjects with baseline levels of TGF-β1 in BAL samples include subjects from an unrelated kindred with familial pulmonary fibrosis (F11), including two individuals with a rare mutation in telomerase (TERT R865H) that is associated with adult-onset pulmonary fibrosis (3).”
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“In a study of familial IPF, Tsakiri and colleagues used linkage in two families to locate the disease gene for IPF in chromosome 5, and identified mutations in the telomerase that cosegregated with pulmonary disease ( 28 ).”
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Genetic susceptibility and pulmonary fibrosis
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“Tsakiri et al. [ 11 ] also independently found three missense mutations and one deletion of TERT genes in 44 probands of familial IPF and an additional single mutation in 44 sporadic cases of IPF.”
Background
Metadata
- Authors
- Tsakiri, K. D., Cronkhite, J. T., Kuan, P. J., Xing, C., Raghu, G., Weissler, J. C., Rosenblatt, R. L., Shay, J. W., & Garcia, C. K.
- Affiliations
- *McDermott Center for Human Growth and Development,
- University of Washington Medical Center (US)
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine,
- The University of Texas Southwestern Medical Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-05
- Volume
- 104
- Issue
- 18
- Pages
- 7552-7557
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1855917
- OpenAlex
- W2115176808
- Cited by
- 894
- References
- 35
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 30 · 2023: 35 · 2022: 49 · 2021: 62 · 2020: 54 · 2019: 43 · 2018: 45 · 2017: 41 · 2016: 40 · 2015: 61 · 2014: 50 · 2013: 50 · 2012: 53
- FWCI
- 47.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50CA75907, P50CA070907)
- National Center for Research Resources (K23RR020632)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Keywords
- idiopathic pulmonary fibrosis, telomerase reverse transcriptase, TERC, telomerase RNA, telomere shortening, genetic linkage, familial pulmonary fibrosis, missense mutations, frameshift mutation, interstitial lung disease, genetic susceptibility, chromosome 5
- MeSH terms
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Animals, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, Pulmonary Fibrosis, Sequence Alignment, Telomere, Age of Onset, Telomerase
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