Journal Article

Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations

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

2010

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Age / Aged / Aged, 80 and over / Aging / Bone marrow / Cancer / Carrier lifetime / Cell division / Chromosomes / Cigarette smoking / Critical care / Deoxyribonucleic acid / Diagnosis / DNA / Dyskeratosis / Enzymes / Epigenetic inheritance / Epigenetics / Family / Family medical history / Female / Females / Fibrosis / Gene mutation / Genetic aspects / Genetics and Genomics / Genetics and Genomics/Epigenetics / Genetics and Genomics/Medical Genetics / Heredity / Heterozygote / Humans / Identification methods / Internal medicine / Leukocytes / Life expectancy / Life span / Liver / Liver diseases / Lung diseases / Male / Males / Medical prognosis / Medical records / Medicine / Middle Aged / Mutation / Mutation - genetics / Nucleotides / Pedigree / Phenotype / Phenotypes / Pulmonary fibrosis / Pulmonary Fibrosis - diagnostic imaging / Pulmonary Fibrosis - enzymology / Pulmonary Fibrosis - genetics / Pulmonary Fibrosis - physiopathology / Radiographs / Radiography / Respiratory Function Tests / Respiratory Medicine / Respiratory Medicine/Interstitial Lung Diseases / Respiratory tract diseases / Smoking / Surgery / Telomerase / Telomerase - genetics / Telomere - metabolism / Telomeres / White blood cells / Young Adult