Adult-onset pulmonary fibrosis caused by mutations in telomerase

Abstract

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.genetics ͉ idiopathic pulmonary fibrosis ͉ telomeres ͉ aging

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…It has also been documented that telomere shortening correlates with age-related pathology and reduced human lifespan (Cawthon et al, 2003;Collerton et al, 2007). Lastly, mutations in human telomerase genes lead to telomere shortening, stem cell defects, impaired organ maintenance and a shortened lifespan (Armanios et al, 2007;Tsakiri et al, 2007;Vulliamy et al, 2004). Together, these data strongly indicate that human telomere reserves are limited.…”

Actions of human telomerase beyond telomeres

“…Inhibition of telomerase in telomerase positive cancer cells can lead to the induction of cell death [20][21][22]. Finally, mutations in either hTR or TERT are associated with many premature aging phenotypes leading to human diseases [23][24][25]. Moreover, telomerase knockout mice and hTERT transgenic mice provided compelling evidence of critical roles of telomerase in aging and cancer [26].…”

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

“…To date, mutations in seven telomerase and telomere genes have been shown to cause familial lung disease; together, they explain one-third of the inheritance in familial pulmonary fibrosis. They include genes that encode the essential telomerase components: TERT, the catalytic component, and TR, the telomerase RNA (21)(22)(23). Three other genes when mutated disrupt TR stability, processing, and biogenesis: DKC1, PARN, and NAF1, respectively (24)(25)(26)(27).…”