Adult-onset pulmonary fibrosis caused by mutations in telomerase

doi:10.1073/pnas.0701009104

Adult-onset pulmonary fibrosis caused by mutations in telomerase

*McDermott Center for Human Growth and Development,
^†Center for Clinical Sciences,
^§Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine,
^¶Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; and
^‡Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, 1959 NE Pacific, Seattle, WA 98195-6522

Edited by Michael S. Brown, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 26, 2007 (received for review February 2, 2007)

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: christine.garcia{at}utsouthwestern.edu
Author contributions: J.W.S. and C.K.G. designed research; K.D.T., J.T.C., P.J.K., and C.X. performed research; G.R., J.C.W., and R.L.R. contributed new reagents/analytic tools; and J.W.S. and C.K.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0701009104/DC1.
Abbreviations:

DKC,

dyskeratosis congenita;

IPF,

idiopathic pulmonary fibrosis;

LOD,

logarithm of odds;

TRAP,

telomere repeat amplification protocol;

TRF,

terminal restriction fragment.
Freely available online through the PNAS open access option.