Progressive Lung Disease and Surfactant Dysfunction with a Deletion in Surfactant Protein C Gene

• Published in: American journal of respiratory cell and molecular biology Vol. 30; no. 6; pp. 771 - 776
• Main Authors: Hamvas, Aaron, Nogee, Lawrence M, White, Frances V, Schuler, Pamela, Hackett, Brian P, Huddleston, Charles B, Mendeloff, Eric N, Hsu, Fong-Fu, Wert, Susan E, Gonzales, Linda W, Beers, Michael F, Ballard, Philip L
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01.06.2004; American Thoracic Society
• Subjects: Adult; Animals; Child; Disease Progression; Exons; Female; Humans; Infant; Lung - metabolism; Lung - pathology; Lung - ultrastructure; Lung Diseases, Interstitial - genetics; Lung Diseases, Interstitial - pathology; Lung Transplantation; Male; Mice; Mutation; Peptides - metabolism; Pulmonary Surfactant-Associated Protein C - genetics; Pulmonary Surfactant-Associated Protein C - metabolism; Pulmonary Surfactants - metabolism; RNA - metabolism
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2003-0323OC

Mutations in the surfactant protein (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-mo-old infant with progressive ILD. An in-frame 9-bp 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 (20 mN/m, normal < 5 mN/m). Type II cells contained normal and disorganized appearing lamellar bodies by electron microscopy. 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.