A novel dyskerin (DKC1) mutation is associated with Familial Interstitial Pneumonia


Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified an FIP kindred 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.


DNA was isolated from peripheral blood mononuclear cells or paraffin-embedded lung block and PCR-based sequencing of DKC1, NOP10, TINF2 and NHP2 was performed. Peripheral blood mononuclear cell telomere length was measured by southern blot. Alveolar epithelial cell (AEC) telomere length was measured by fluorescence-in-situ-hydridization. Dyskerin and hTR expression in lymphoblastoid cell lines were measured by qPCR.


The proband was a 69 year-old man with dyspnea, restrictive pulmonary function tests and reticular changes on high-resolution CT. 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. Sequencing of dyskerin (DKC1) revealed that both affected siblings shared a novel A to G 1213 transition 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 mechanism by which dyskerin contributes to the development of lung fibrosis is warranted.

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mer 12 marzo 2014
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