title: Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene.
abstract: 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.
authors.affiliation: Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, 1 Children's Place, St. Louis, MO 63110, USA. hamvas@kids.wustl.edu
authors.forename: Aaron
authors.initials: A
authors.lastname: Hamvas
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nogee
authors.forename: Frances V
authors.initials: FV
authors.lastname: White
authors.forename: Pamela
authors.initials: P
authors.lastname: Schuler
authors.forename: Brian P
authors.initials: BP
authors.lastname: Hackett
authors.forename: Charles B
authors.initials: CB
authors.lastname: Huddleston
authors.forename: Eric N
authors.initials: EN
authors.lastname: Mendeloff
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Linda W
authors.initials: LW
authors.lastname: Gonzales
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.forename: Philip L
authors.initials: PL
authors.lastname: Ballard
mesh_terms: D000328:Adult; D000818:Animals; D002648:Child; D018450:Disease Progression; D005091:Exons; D005260:Female; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D009154:Mutation; D010455:Peptides / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics* / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012313:RNA / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants; C489679:SFTPC protein, human; C489680:Sftpc protein, mouse; D012313:RNA