Proceedings of the National Academy
of Sciences, USA
Proc Natl Acad Sci USA. 2007 May 1;104(18):7552-7. Epub 2007 Apr 25.
Adult-onset pulmonary fibrosis
caused by Mutations in Telomerase
Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL,
Shay JW, Garcia CK
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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