Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations

Abstract

BackgroundTelomerase 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 FindingsWe 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.ConclusionsA 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.

Telomerase mutations in smokers with severe emphysema

“…Among 83 cases that fulfilled these criteria, we found no homozygous SERPINA1 mutations, but we identified an individual with a heterozygous missense TERT mutation: His925Gln ( Figure 1A). This mutation was previously reported in several members of a family with pulmonary fibrosis and liver disease (19). In total, across the two COPD cohorts, there were three TERT variants among the severe COPD cases (3 of 292, 1%), and all of them fell in conserved motifs within the telomerase reverse transcriptase domain (Supplemental Figure 3).…”

Telomere dysfunction causes alveolar stem cell failure

“…*P < 0.05, **P < 0.01, ***P < 0.001, Student's t test. (7,8,36,37). The cellular responses to telomere dysfunction are also distinct.…”

Epigenetic Modifications in Hepatic Stellate Cells Contribute to Liver Fibrosis

“…This comparison clarifies the fact that the telomere length between liver fibrosis patients and normal persons is distinct and related with the methylation status of individuals. Regard ing the issue of inheritance, another investigation compared telomere length between normal people and "special" people, who have sibship with hepatopathy patients (Diaz de Leon et al 2010). The outcome showed "special" people have shorter telomere than normal person.…”