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Cited by 894Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisTelomeres, Telomerase, and SenescenceOccupational and environmental lung diseases

Adult-onset pulmonary fibrosis caused by mutations in telomerase

Open access
Tsakiri, Kalliopi D., Cronkhite, Jennifer T., Kuan, Phillip J., Xing, Chao, Raghu, Ganesh, Weissler, Jonathan C., Rosenblatt, Randall L., Shay, Jerry W. +1 more·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0701009104PMC PMC1855917
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Abstract

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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1073/pnas.0701009104

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 31 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    Sequencing TERT revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    A heterozygous mutation in TERC was found in one family.

    “A heterozygous mutation in TERC also was found in one family.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Linkage analysis mapped the disease gene in two families to chromosome 5p15 with a maximal LOD score of 2.8.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT.

    “Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations.

    “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).”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 3
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 10

  • The quote only partly states this claim.

    Findingown data
    § Results

    Four additional sequence variations, including three missense mutations and one 177-bp deletion, were found in TERT in probands of 44 additional families.

    “Four additional sequence variations, including three missense mutations and one 177-bp deletion, were found (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Results

    None of the seven mutations were found in 94 locally collected, ethnically matched individuals, nor in 200 patients with aplastic anemia or a multiethnic panel of 528 individuals sequenced as controls.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Discussion

    All individuals with TERT or TERC mutations developed pulmonary fibrosis during their adult years with no history of pediatric lung disease, in contrast with kindreds associated with surfactant protein C mutations.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

      Not checked in the free run.

    • cites [19] Nogee LM, Dunbar AE, III, Wert SE, Askin F, Hamvas A, Whitsett JA. N Engl J Med. 2001;344:573–579. doi: 10.1056/NEJM200102223440805. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § Discussion

    None of the individuals with TERT or TERC mutations had aplastic anemia, but several exhibited a mild to moderate anemia and one individual developed neutropenia after lung transplantation.

    “None had aplastic anemia but several exhibited a mild to moderate anemia and one individual developed neutropenia after lung transplantation.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Results

    One additional missense mutation was identified in TERT in 44 individuals with sporadic interstitial lung disease, involving the same arginine at codon 865 found to be mutated in family F11.

    “One additional missense mutation was identified involving the same arginine at codon 865 found to be mutated in family F11.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Another individual with a TERT mutation in family 11 had very short TRFs but did not have IPF; this individual had cirrhosis of unknown etiology.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    The proband of family F31 was heterozygous for a deletion of thymidine at position 2240 in the cDNA, which creates a frameshift and is predicted to result in a truncated protein missing half of the reverse-transcriptase domain and the entire C-terminal region.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    The V747fs mutation missing half the reverse transcriptase domain and the E1116fs mutation missing the C-terminal E-IV domain had very little detectable telomerase activity.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § Results

    This TERC 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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingnone given
    § Discussion

    A number of individuals had evidence of axial osteoporosis; in many cases, this diagnosis preceded or was determined in the absence of lung disease.

    “A number of individuals had evidence of axial osteoporosis; in many cases, this diagnosis preceded or was determined in the absence of lung disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Results

    Some family members with TERT mutations exhibited other clinical features of DKC, such as osteoporosis/osteopenia, anemia and cancer, but none of the affected individuals had the mucocutaneous lesions typical of DKC.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Dokal I. Br J Haematol. 2000;110:768–779. doi: 10.1046/j.1365-2141.2000.02109.x. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Discussion

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

    • cites [17] Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, Read EJ, Lansdorp PM, Young NS. Lancet. 2003;362:1628–1630. doi: 10.1016/S0140-6736(03)14797-6. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingown data
    § Results

    One proband of a Caucasian family (F61) was heterozygous for an adenosine and guanine at position 37 in TERC.

    “One proband of a Caucasian family (F61) was heterozygous for an adenosine and guanine at position 37.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Results

    TERT 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.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [7] Dokal I. Br J Haematol. 2000;110:768–779. doi: 10.1046/j.1365-2141.2000.02109.x. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    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).

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Marshall RP, Puddicombe A, Cookson WO, Laurent GJ. Thorax. 2000;55:143–146. doi: 10.1136/thorax.55.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [5] Johnston ID, Prescott RJ, Chalmers JC, Rudd RM. Thorax. 1997;52:38–44. doi: 10.1136/thx.52.1.38. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given
    § Materials and Methods

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § Discussion

    Oxidative damage may in part explain why lung disease is the predominant phenotype and why smoking may exacerbate this disease.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    The pathologic features of IPF suggest that the lung injury is focal, affecting scattered portions of the lung parenchyma and recurring over many years.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § Materials and Methods

    Repeat experiments showed the same relative trend of TRAP activities.

    “Repeat experiments showed the same relative trend of TRAP activities.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Results

    Multiple different mutations in TERC have been described for patients with DKC.

    “Multiple different mutations in TERC have been described for patients with DKC (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Discussion

    Pulmonary fibrosis appears to be a human-specific manifestation of telomerase deficiency.

    “Pulmonary fibrosis appears to be a human-specific manifestation of telomerase deficiency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data
    § Materials and Methods

    Call rates varied from 99.7-100% for Autopure-purified DNA and between 72-98% for whole-genome-amplified DNA extracted from archival samples.

    “Call rates varied from 99.7–100% for Autopure-purified DNA and between 72–98% for whole-genome-amplified DNA extracted from archival samples.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Discussion

    Telomerase may be a marker for identifying resident stem cells that promote regeneration and prevent premature aging of the lung.

    “Telomerase may be a marker for identifying resident stem cells that promote regeneration and prevent premature aging of the lung.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    Smoking causes telomere shortening in a dose-dependent manner and is associated with familial interstitial pneumonia.

    “Smoking causes telomere shortening in a dose-dependent manner (22) and is associated with familial interstitial pneumonia (23).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Morla M, Busquets X, Pons J, Sauleda J, MacNee W, Agusti AG. Eur Respir J. 2006;27:525–528. doi: 10.1183/09031936.06.00087005. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [23] Steele MP, Speer MC, Loyd JE, Brown KK, Herron A, Slifer SH, Burch LH, Wahidi MM, Phillips JA, III, Sporn TA, et al. Am J Respir Crit Care Med. 2005;172:1146–1152. doi: 10.1164/rccm.200408-1104OC. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    A recent trial with high doses of the antioxidant acetylcysteine appeared to attenuate the progression of IPF.

    “Interestingly, a recent trial with high doses of the antioxidant acetylcysteine appeared to attenuate the progression of IPF (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    This report provides previously undescribed molecular insight into the pathogenesis of IPF and expands the scope of diseases caused by mutations in telomerase.

    “This report provides previously undescribed molecular insight into the pathogenesis of IPF and expands the scope of diseases caused by mutations in telomerase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Results

    Telomere length is influenced by many different factors, including age and the number of generations the mutation is transmitted.

    “Telomere length is influenced by many different factors, including age (13, 14) and the number of generations the mutation is transmitted (6, 15).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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

      Not checked in the free run.

    • cites [14] Harley CB, Futcher AB, Greider CW. Nature. 1990;345:458–460. doi: 10.1038/345458a0. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [15] Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. Nat Genet. 2004;36:447–449. doi: 10.1038/ng1346. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given
    § Materials and Methods

    This study was approved by the University of Texas Southwestern Institutional Review Board and written informed consent was obtained from all participants.

    “This study was approved by the University of Texas Southwestern Institutional Review Board. Written informed consent was obtained from all participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    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.

    “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.”
    Quote in the paperSubstantial claim
30 of 30

  • 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.”
1 of 1

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?

  • TERT or TR mutations are found in 8-15% of familial IPF and 1-3% of sporadic IPF cases.

    “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]

  • Patients with dyskeratosis congenita and aplastic anaemia show decreased telomerase activity and shortened telomeres owing to mutations in the TERC and TERT telomerase genes.

    “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]

  • 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, idiopathic pulmonary fibrosis and the rarer dyskeratosis congenita syndrome.

    “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]

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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)
ORCID
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
DOI
10.1073/pnas.0701009104
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
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor)
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
  • Health Sciences › Medicine › Physiology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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