Tsakiri, K. D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl Acad. Sci. USA 104, 7552-7557

McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2007; 104(18):7552-7. DOI: 10.1073/pnas.0701009104
Source: PubMed


Idiopathic pulmonary fibrosis (IPF) is an adult-onset, lethal, scarring lung disease of unknown etiology. Some individuals with IPF have a familial disorder that segregates as a dominant trait with incomplete penetrance. Here we used linkage to map the disease gene in two families to chromosome 5. Sequencing a candidate gene within the interval, TERT, revealed a missense mutation and a frameshift mutation that cosegregated with pulmonary disease in the two families. TERT encodes telomerase reverse transcriptase, which together with the RNA component of telomerase (TERC), is required to maintain telomere integrity. Sequencing the probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed five other mutations in TERT. A heterozygous mutation in TERC also was found in one family. Heterozygous carriers of all of the mutations in TERT or TERC had shorter telomeres than age-matched family members without the mutations. Thus, mutations in TERT or TERC that result in telomere shortening over time confer a dramatic increase in susceptibility to adult-onset IPF.

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    • "Armanios et al. (32) studied families with IPF and demonstrated that telomerase was inactive, using mutations in the genes that encode telomerase components. Tsakiri et al. (33) sequenced the probands of 44 unrelated families and 44 sporadic cases of interstitial lung disease and revealed mutations in telomerase reverse transcriptase (TERT) or telomerase RNA component that result in telomere shortening over time and confer a dramatic increase in the susceptibility to adult-onset IPF. Subsequently, El-Chemaly et al. (34) identified a novel heterozygous mutation in TERT (R1084P), which results in telomerase dysfunction and short telomeres. "
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    ABSTRACT: Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis.
    Full-text · Article · Jun 2014 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
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    • "). IPF is characterized by progressive failure of the lung coincident with fibrosis and inflammation (Armanios et al., 2007). Inherited mutations in TERC and TERT explain 8–20% of familial cases of IPF, as well as a small proportion of sporadic IPF cases (Tsakiri et al., 2007). 37% of familial cases and 25% of sporadic cases are associated with telomere lengths lower than the 10th percentile of the general population, suggesting that there is a significant number of IPF cases associated with impaired telomere maintenance with as-yet undiscovered genetic or environmental causes (Cronkhite et al., 2008). "
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    ABSTRACT: A constellation of related genetic diseases are caused by defects in the telomere maintenance machinery. These disorders, often referred to as telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease. Several new causes of these disorders have been recently discovered, and a number of related syndromes may be unrecognized telomeropathies. Progress in the clinical understanding of telomeropathies has in turn driven progress in the basic science of telomere biology. In addition, the pattern of genetic anticipation in some telomeropathies generates thought-provoking questions about the way telomere length impacts the course of these diseases.
    Full-text · Article · May 2014 · The Journal of Cell Biology
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    • "Familial forms of idiopathic pulmonary fibrosis (IPF) account for 2–20% of IPF patients, supporting a strong genetic component in the development of the disease [reviewed in Kropski et al. (2013)]. Investigations on families have identified genetic variants in SFTPC (encoding surfactant protein C), SFTPA2 (encoding surfactant protein A2), MUC5B (encoding a mucin constituent of the mucus), as well as TERT and TERC (encoding components of the telomerase complex) to be associated with pulmonary fibrosis (Nogee et al., 2001; Thomas et al., 2002; Armanios et al., 2007; Tsakiri et al., 2007; Wang et al., 2009; van Moorsel et al., 2010; Ono et al., 2011; Seibold et al., 2011). The genetic association of genetic polymorphisms in MUC5B-MUC2-TOLLIP as well as TERT and TERC loci with high risk for pulmonary fibrosis has been confirmed by recent results from GWAS comparing 4683 controls and 1616 cases of fibrotic idiopathic interstitial pneumonias (IIP) including 77% of IPF cases with independent replication cohort (Fingerlin et al., 2013). "
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    ABSTRACT: Genetic studies of human diseases have identified multiple genetic risk loci for various fibrotic diseases. This has provided insights into the myriad of biological pathways potentially involved in disease pathogenesis. These discoveries suggest that alterations in immune responses, barrier function, metabolism and telomerase activity may be implicated in the genetic risks for fibrotic diseases. In addition to genetic disease-risks, the identification of genetic disease-modifiers associated with disease complications, severity or prognosis provides crucial insights into the biological processes implicated in disease progression. Understanding the biological processes driving disease progression may be critical to delineate more effective strategies for therapeutic interventions. This review provides an overview of current knowledge and gaps regarding genetic disease-risks and genetic disease-modifiers in human fibrotic diseases.
    Full-text · Article · Dec 2013 · Frontiers in Pharmacology
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