Telomere lengths, pulmonary fibrosis and telomerase (TERT) Mutations

Alberto Diaz de Leon, Jennifer T. Cronkhite, Anna Luise A Katzenstein, J. David Godwin, Ganesh Raghu, Craig S. Glazer, Randall L. Rosenblatt, Carlos E. Girod, Edward R. Garrity, Chao Xing, Christine Kim Garcia

Research output: Contribution to journalArticle

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Abstract

Background: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. Methods and Findings: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. Conclusions: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a ''telomeropathy'' caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.

Original languageEnglish (US)
Article numbere10680
JournalPLoS One
Volume5
Issue number5
DOIs
StatePublished - 2010

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telomerase
Pulmonary Fibrosis
Telomerase
telomeres
Telomere
fibrosis
Biopsy
lungs
mutation
Mutation
Idiopathic Pulmonary Fibrosis
Chromosomes
Tobacco Products
Liver
Assays
Bone
Nucleotides
Genes
Telomere Shortening
inheritance (genetics)

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Telomere lengths, pulmonary fibrosis and telomerase (TERT) Mutations. / Diaz de Leon, Alberto; Cronkhite, Jennifer T.; Katzenstein, Anna Luise A; Godwin, J. David; Raghu, Ganesh; Glazer, Craig S.; Rosenblatt, Randall L.; Girod, Carlos E.; Garrity, Edward R.; Xing, Chao; Garcia, Christine Kim.

In: PLoS One, Vol. 5, No. 5, e10680, 2010.

Research output: Contribution to journalArticle

Diaz de Leon, A, Cronkhite, JT, Katzenstein, ALA, Godwin, JD, Raghu, G, Glazer, CS, Rosenblatt, RL, Girod, CE, Garrity, ER, Xing, C & Garcia, CK 2010, 'Telomere lengths, pulmonary fibrosis and telomerase (TERT) Mutations', PLoS One, vol. 5, no. 5, e10680. https://doi.org/10.1371/journal.pone.0010680
Diaz de Leon, Alberto ; Cronkhite, Jennifer T. ; Katzenstein, Anna Luise A ; Godwin, J. David ; Raghu, Ganesh ; Glazer, Craig S. ; Rosenblatt, Randall L. ; Girod, Carlos E. ; Garrity, Edward R. ; Xing, Chao ; Garcia, Christine Kim. / Telomere lengths, pulmonary fibrosis and telomerase (TERT) Mutations. In: PLoS One. 2010 ; Vol. 5, No. 5.
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abstract = "Background: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. Methods and Findings: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60{\%} of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74{\%} of cases and a pathologic pattern of UIP is seen in 86{\%} of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. Conclusions: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a ''telomeropathy'' caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.",
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AU - Raghu, Ganesh

AU - Glazer, Craig S.

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AB - Background: Telomerase is an enzyme that catalyzes the addition of nucleotides on the ends of chromosomes. Rare loss of function mutations in the gene that encodes the protein component of telomerase (TERT) have been described in patients with idiopathic pulmonary fibrosis (IPF). Here we examine the telomere lengths and pulmonary fibrosis phenotype seen in multiple kindreds with heterozygous TERT mutations. Methods and Findings: We have identified 134 individuals with heterozygous TERT mutations from 21 unrelated families. Available medical records, surgical lung biopsies and radiographs were evaluated retrospectively. Genomic DNA isolated from circulating leukocytes has been used to measure telomere lengths with a quantitative PCR assay. We find that telomere lengths of TERT mutation carriers decrease in an age-dependent manner and show progressive shortening with successive generations of mutation inheritance. Family members without TERT mutations have a shorter mean telomere length than normal, demonstrating epigenetic inheritance of shortened telomere lengths in the absence of an inherited TERT mutation. Pulmonary fibrosis is an age-dependent phenotype not seen in mutation carriers less than 40 years of age but found in 60% of men 60 years or older; its development is associated with environmental exposures including cigarette smoking. A radiographic CT pattern of usual interstitial pneumonia (UIP), which is consistent with a diagnosis of IPF, is seen in 74% of cases and a pathologic pattern of UIP is seen in 86% of surgical lung biopsies. Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis. Overall, TERT mutation carriers demonstrate reduced life expectancy, with a mean age of death of 58 and 67 years for males and females, respectively. Conclusions: A subset of pulmonary fibrosis, like dyskeratosis congenita, bone marrow failure, and liver disease, represents a ''telomeropathy'' caused by germline mutations in telomerase and characterized by short telomere lengths. Family members within kindreds who do not inherit the TERT mutation have shorter telomere lengths than controls, demonstrating epigenetic inheritance of a shortened parental telomere length set-point.

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