title: A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia.
abstract: 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.
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN. Electronic address: Jon.Kropski@vanderbilt.edu.
authors: Jonathan A
authors: JA
authors: Kropski
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors: Daphne B
authors: DB
authors: Mitchell
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors: Cheryl
authors: C
authors: Markin
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors: Vasiliy V
authors: VV
authors: Polosukhin
authors: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN.
authors: Leena
authors: L
authors: Choi
authors: Department of Pediatrics, Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.
authors: Joyce E
authors: JE
authors: Johnson
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Department of Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, TN.
authors: William E
authors: WE
authors: Lawson
authors: Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN; Department of Pediatrics, Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.
authors: John A
authors: JA
authors: Phillips
authors: Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors: Joy D
authors: JD
authors: Cogan
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Department of Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, TN; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN.
authors: Timothy S
authors: TS
authors: Blackwell
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
authors: James E
authors: JE
authors: Loyd
mesh_terms: D000368:Aged; D001706:Biopsy; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D003937:Diagnosis, Differential; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D017563:Lung Diseases, Interstitial / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D004247:DNA