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A Novel Dyskerin (DKC1) Mutation Is Associated With Familial Interstitial PneumoniaDKC1 Mutation in Familial Interstitial Pneumonia

Jonathan A. Kropski, MD; Daphne B. Mitchell, MS; Cheryl Markin, BS; Vasiliy V. Polosukhin, MD; Leena Choi, PhD; Joyce E. Johnson, MD; William E. Lawson, MD; John A. Phillips, III, MD; Joy D. Cogan, PhD; Timothy S. Blackwell, MD; James E. Loyd, MD
Author and Funding Information

From the Department of Medicine (Drs Kropski, Polosukhin, Lawson, Blackwell, and Loyd and Mss Mitchell and Markin), Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine; Department of Veterans Affairs Medical Center (Drs Lawson and Blackwell); and the Division of Medical Genetics and Genomic Medicine (Drs Phillips and Cogan), Department of Pediatrics, Department of Pathology, Microbiology and Immunology (Drs Johnson and Phillips), Department of Cancer Biology (Dr Blackwell), Department of Cell and Developmental Biology (Dr Blackwell), and Department of Biostatistics (Dr Choi), Vanderbilt University School of Medicine, Nashville, TN.

Correspondence to: Jonathan A. Kropski, MD, 1161 21st Ave S, T-1218 Medical Center N, Vanderbilt University Medical Center, Nashville, TN 37232; e-mail: Jon.Kropski@vanderbilt.edu


Some of these results have been presented previously in abstract form (Kropski JA, Mitchell DB, Markin C, et al. Am J Crit Care Med. 2013;187:A1081).

Funding/Support: The study was supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute [Grants HL92870, HL085317, and HL094296 to Dr Blackwell and Grant HL105479 to Dr Lawson] and the Department of Veterans Affairs (grants to Drs Lawson and Blackwell).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(1):e1-e7. doi:10.1378/chest.13-2224
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Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified a kindred with FIP with short telomeres who did not carry a mutation in known FIP genes TERT or hTR. We performed targeted sequencing of other telomere-related genes to identify the genetic basis of FIP in this kindred. The proband was a 69 year-old man with dyspnea, restrictive pulmonary function test results, and reticular changes on high-resolution CT scan. An older male sibling had died from IPF. The proband had markedly shortened telomeres in peripheral blood and undetectably short telomeres in alveolar epithelial cells. Polymerase chain reaction-based sequencing of NOP10, TINF2, NHP2, and DKC1 revealed that both affected siblings shared a novel A to G 1213 transition in DKC1 near the hTR binding domain that is predicted to encode a Thr405Ala amino acid substitution. hTR levels were decreased out of proportion to DKC1 expression in the T405A DKC1 proband, suggesting this mutation destabilizes hTR and impairs telomerase function. This DKC1 variant represents the third telomere-related gene identified as a genetic cause of FIP. Further investigation into the mechanism by which dyskerin contributes to the development of lung fibrosis is warranted.

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