Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations

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...

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Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873288/
https://www.ncbi.nlm.nih.gov/pubmed/20502709
http://dx.doi.org/10.1371/journal.pone.0010680
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author 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
author_facet 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
author_sort Diaz de Leon, Alberto
collection PubMed
description 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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spelling pubmed-28732882010-05-25 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 PLoS One Research Article 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. Public Library of Science 2010-05-19 /pmc/articles/PMC2873288/ /pubmed/20502709 http://dx.doi.org/10.1371/journal.pone.0010680 Text en Diaz de Leon et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
title Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations
title_full Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations
title_fullStr Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations
title_full_unstemmed Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations
title_short Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations
title_sort telomere lengths, pulmonary fibrosis and telomerase (tert) mutations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873288/
https://www.ncbi.nlm.nih.gov/pubmed/20502709
http://dx.doi.org/10.1371/journal.pone.0010680
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