Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest 2015 May;147(5):1361-1368
Date
12/30/2014Pubmed ID
25539146Pubmed Central ID
PMC4420184DOI
10.1378/chest.14-1947Scopus ID
2-s2.0-84929484543 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
BACKGROUND: Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases.
METHODS: We identified a family with pulmonary fibrosis, idiopathic infertility, and short telomeres.
RESULTS: Exome sequencing of blood-derived DNA revealed two mutations in the telomere-binding protein TINF2. The first was a 15-base-pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele, indicating that the deletion seen in the blood was acquired and may have a protective advantage because it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to that described for Fanconi anemia. No mutations were identified in over 40 uncharacterized pulmonary fibrosis probands suggesting that mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of TERT and TR mutation carriers (five of 45).
CONCLUSIONS: Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis and suggest that infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.
Author List
Alder JK, Stanley SE, Wagner CL, Hamilton M, Hanumanthu VS, Armanios MAuthor
Christa Wagner PhD Director, Assistant Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ExomeFemale
Humans
Infertility
Male
Middle Aged
Mutation, Missense
Pedigree
Pulmonary Fibrosis
Retrospective Studies
Sequence Deletion
Telomere-Binding Proteins
