Published ahead of print on December 4, 2003, doi:10.1165/rcmb.2003-0323OC Am. J. Respir. Cell Mol. Biol., Volume 30, Number 6, June 2004, 771-776 A more recent version of this article appeared on June 1, 2004
Submitted on August 28, 2003 Progressive lung disease and surfactant dysfunction with a deletion of surfactant protein C geneAaron Hamvas1*,1 Pediatrics, Washington University/St. Louis Children's Hospital, St. Louis, MO, USA, 2 Pediatrics, Johns Hopkins University, Baltimore, MD, USA, 3 Pathology, Washington University, St. Louis, MO, USA, 4 Surgery, Washington University, St. Louis, MO, USA, 5 Medicine, Washington University, St. Louis, MO, USA, 6 Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA, 7 Pediatrics, University of Pennsylvania/Children's Hospital of Philadelphia, Philadelphia, PA, USA, 8 Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA * To whom correspondence should be addressed. E-mail: hamvas{at}kids.wustl.edu.
Mutations in the surfactant protein-C (SP-C) gene are responsible for familial and sporadic interstitial lung disease (ILD). The consequences of such mutations on pulmonary surfactant composition and function are poorly understood. To determine the effects of a mutation in the SP-C gene on surfactant, we obtained lung tissue at the time of transplantation from a 14 month old infant with progressive ILD. An in-frame 9-base pair deletion spanning codons 91-93 in Exon 3 of the SP-C gene was present on one allele; neither parent carried this deletion. SP-C mRNA was present in normal size and amount. By immunofluorescence, proSP-C was aggregated within alveolar Type II cells in a compartment separate from SP-B. In airway surfactant, there was little or no mature SP-B or SP-C; SP-A content was increased. Minimum surface tension was increased (20mN/m, normal <5 mN/m). Type II cells contained normal and disorganized appearing lamellar bodies by electron microscopy (EM). This spontaneous deletion on one allele of the SP-C gene was associated with sporadic ILD and abnormalities in surfactant composition and function. We propose that a dominant negative effect on surfactant protein metabolism and function results from aggregation of misfolded proSP-C and subsequent cell injury and inflammation.
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