James Loyd
Faculty Member
Last active: 2/12/2015

A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia.

Kropski JA, Mitchell DB, Markin C, Polosukhin VV, Choi L, Johnson JE, Lawson WE, Phillips JA, Cogan JD, Blackwell TS, Loyd JE
Chest. 2014 146 (1): e1-e7

PMID: 24504062 · PMCID: PMC4077414 · DOI:10.1378/chest.13-2224

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.

MeSH Terms (14)

Aged Biopsy Cell Cycle Proteins Diagnosis, Differential DNA Humans In Situ Hybridization, Fluorescence Lung Diseases, Interstitial Male Mutation Nuclear Proteins Pedigree Polymerase Chain Reaction Tomography, X-Ray Computed

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