TY - JOUR
T1 - Adult-onset pulmonary fibrosis caused by mutations in telomerase
AU - Tsakiri, Kalliopi D.
AU - Cronkhite, Jennifer T.
AU - Kuan, Phillip J.
AU - Xing, Chao
AU - Raghu, Ganesh
AU - Weissler, Jonathan C.
AU - Rosenblatt, Randall L.
AU - Shay, Jerry W.
AU - Garcia, Christine Kim
PY - 2007/5/1
Y1 - 2007/5/1
N2 - 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.
AB - 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.
KW - Aging
KW - Genetics
KW - Idiopathic pulmonary fibrosis
KW - Telomeres
UR - http://www.scopus.com/inward/record.url?scp=34250614359&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250614359&partnerID=8YFLogxK
U2 - 10.1073/pnas.0701009104
DO - 10.1073/pnas.0701009104
M3 - Article
C2 - 17460043
AN - SCOPUS:34250614359
SN - 0027-8424
VL - 104
SP - 7552
EP - 7557
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -