Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene

Pediatr Res. 2005 Jan;57(1):89-98. doi: 10.1203/01.PDR.0000147567.02473.5A. Epub 2004 Nov 19.


Human surfactant protein C (hSP-C(1-197)) is synthesized as a 197 amino acid proprotein and cleaved to a mature 3.7 kD form. Although interstitial lung disease in patients with mutations of the hSP-C gene is becoming increasingly recognized, the mechanisms linking molecular events with clinical pathogenesis are not fully defined. We describe a full-term infant with respiratory insufficiency associated with a spontaneous heterozygous mutation resulting in a substitution of lysine for glutamic acid at position 66 (= E66K) of the proximal hSP-C COOH flanking propeptide. Lung histology and biochemical studies of the index patient (hSP-C(E66K)) revealed nonspecific interstitial pneumonia, increased alveolar total phospholipid lacking phosphatidylglycerol, and increased surfactant protein A. Localization of proSP-C from lung sections prepared from this patient using immunofluorescence and immunogold electron microscopy revealed abnormal proSP-C staining in endosomal-like vesicles of type II cells distinct from SP-B. To evaluate the effect of the E66K substitution on intracellular trafficking of proSP-C, fusion proteins consisting of enhanced green fluorescent protein (EGFP) and hSP-C(1-197) (wild type) or mutant hSP-C(E66K) were generated and transfected into A549 cells. EGFP/hSP-C(1-197) was expressed within CD-63-positive, EEA-1-negative vesicles, whereas EGFP/hSP-C(E66K) localized to EEA-1 positive vesicles. The E66K substitution is representative of a new class of SP-C mutation associated with interstitial lung disease that is diverted from the normal biosynthetic pathway. We propose that, similar to other storage disorders, lung injury results from induction of a toxic gain of function induced by the mutant product that is subject to genetic modifiers and environmental influences.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • Bronchoalveolar Lavage
  • Cell Line, Tumor
  • DNA / metabolism
  • DNA Primers / chemistry
  • DNA, Complementary / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Glutamic Acid / chemistry
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Infant
  • Lung / pathology
  • Lung Diseases, Interstitial / genetics*
  • Lung Diseases, Interstitial / pathology*
  • Lysine / chemistry
  • Male
  • Microscopy, Fluorescence
  • Microscopy, Immunoelectron
  • Microscopy, Phase-Contrast
  • Models, Biological
  • Mutation*
  • Phospholipids / metabolism
  • Protein Transport
  • Pulmonary Alveolar Proteinosis / genetics*
  • Pulmonary Alveolar Proteinosis / pathology*
  • Pulmonary Surfactant-Associated Protein C / genetics*
  • Recombinant Fusion Proteins / metabolism
  • Surface-Active Agents / metabolism
  • Time Factors
  • Tomography, X-Ray Computed
  • Transfection


  • DNA Primers
  • DNA, Complementary
  • Phospholipids
  • Pulmonary Surfactant-Associated Protein C
  • Recombinant Fusion Proteins
  • Surface-Active Agents
  • Green Fluorescent Proteins
  • Glutamic Acid
  • DNA
  • Lysine