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

Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis; Department of Pathology and Immunology, Department of Surgery, and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pediatrics, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, and Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Address correspondence to: Aaron Hamvas, M.D., Division of Newborn Medicine, St. Louis Children's Hospital, 1 Children's Place, St. Louis, MO 63110. E-mail: hamvas{at}kids.wustl.edu

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.

Abbreviations: bronchoalveolar lavage, BAL • bronchopulmonary dysplasia, BPD • electron microscopy, EM • endoplasmic reticulum, ER • electrospray ionization, ESI • interstitial lung disease, ILD • pulmonary alveolar proteinosis, PAP • phosphatidylcholine, PC • polymerase chain reaction, PCR • phosphatidylethanolamine, PE • phosphatidylglycerol, PG • phosphatidylinositol, PI • surfactant protein, SP

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