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Previous Volume 356:1317-1326 March 29, 2007 Number 13 Next

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ABSTRACT

Background Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis.

Methods To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR.

Results Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families.

Conclusions Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease.

Source Information

From the Department of Oncology (M.Y.A., C.W.G.), the Graduate Program in Cellular and Molecular Medicine (J.K.A.), the Institute of Genetic Medicine (R.G.I.), and the Department of Molecular Biology and Genetics (C.W.G.), Johns Hopkins University School of Medicine, Baltimore; the Department of Chemistry and Biochemistry (J.J.-L.C., M.X.) and the School of Life Sciences (J.J.-L.C.), Arizona State University, Tempe; the Departments of Pediatrics (J.D.C., J.A.P.) and Medicine (C.M., W.E.L., J.E.L.), Vanderbilt University School of Medicine, Nashville; the Veterans Affairs Medical Center, Nashville (W.E.L.); and the Terry Fox Laboratory (I.V., P.M.L.) and the British Columbia Cancer Agency and the Department of Medicine (P.M.L.), University of British Columbia, Vancouver, BC, Canada.

Address reprint requests to Dr. Armanios at the Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St., CRB 186, Baltimore, MD 21231, or at marmani1{at}jhmi.edu.

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