title: 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.
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors: Kalliopi D
authors: KD
authors: Tsakiri
authors: Jennifer T
authors: JT
authors: Cronkhite
authors: Phillip J
authors: PJ
authors: Kuan
authors: Chao
authors: C
authors: Xing
authors: Ganesh
authors: G
authors: Raghu
authors: Jonathan C
authors: JC
authors: Weissler
authors: Randall L
authors: RL
authors: Rosenblatt
authors: Jerry W
authors: JW
authors: Shay
authors: Christine Kim
authors: CK
authors: Garcia
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016415:Sequence Alignment; D019098:Telomerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics
chemical_list: C509186:TERT protein, human; D019098:Telomerase