Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening (original) (raw)
Related papers
Short telomeres in pulmonary fibrosis: from genetics to clinical significance
Pneumologia (Bucharest, Romania)
Pulmonary fibrosis has been linked molecularly and pathophysiologically by abnormal telomere maintenance. Short telomere lengths are commonly found in both the familial and sporadic forms, telomerase mutations being the most common identifiable genetic cause of the disease. Telomeres are repeated nucleotide sequences that cap the ends of chromosomes and protect them from damage. Telomeres are eroded with cell division and shorten with age. Telomere integrity is mediated by the telomerase complex, a specialized polymerase that adds sequences to the ends of chromosomes. Mutations in the genes encoding telomerase (TERT and TERC) cause pulmonary fibrosis through low telomerase activity, accelerated telomere shortening and exhaustion of lung stem cells. Mutations in TERTor TERC account for only 19% of familial pulmonary fibrosis cases, and it is likely that additional environmental, genetic and epigenetic factors contribute to telomere erosion and to disease phenotype. Identification of ...
Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive
The European respiratory journal, 2016
Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an ea...
The Lancet. Respiratory medicine, 2014
Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival. In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco). 370 patients were enr...
Biomedicines
Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chr...
An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis
American journal of respiratory and critical care medicine, 2017
Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. The aim of this study was to use whole-exome sequencing to improve our understanding of the genetic architecture of pulmonary fibrosis. We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis; clinically classified as IPF according to ATS/ERS/JRS/ALAT guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing non-specific interstitial pneumonia (7.2%). The majority of cases (87%) reported no family history of pulmonary fibrosis. We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 pulmonary fibrosis cases and 4,141 controls drawn from individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes found a study-wide significant (p<4.5x10-7) case-enri...