Skip to main content

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

Publication ,  Journal Article
Stevens, PA; Pettenazzo, A; Brasch, F; Mulugeta, S; Baritussio, A; Ochs, M; Morrison, L; Russo, SJ; Beers, MF
Published in: Pediatr Res
January 2005

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.

Duke Scholars

Published In

Pediatr Res

DOI

ISSN

0031-3998

Publication Date

January 2005

Volume

57

Issue

1

Start / End Page

89 / 98

Location

United States

Related Subject Headings

  • Transfection
  • Tomography, X-Ray Computed
  • Time Factors
  • Surface-Active Agents
  • Recombinant Fusion Proteins
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Alveolar Proteinosis
  • Protein Transport
  • Phospholipids
  • Pediatrics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Stevens, P. A., Pettenazzo, A., Brasch, F., Mulugeta, S., Baritussio, A., Ochs, M., … Beers, M. F. (2005). Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. Pediatr Res, 57(1), 89–98. https://doi.org/10.1203/01.PDR.0000147567.02473.5A
Stevens, Paul A., Andrea Pettenazzo, Frank Brasch, Surafel Mulugeta, Aldo Baritussio, Matthias Ochs, Lake Morrison, Scott J. Russo, and Michael F. Beers. “Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene.Pediatr Res 57, no. 1 (January 2005): 89–98. https://doi.org/10.1203/01.PDR.0000147567.02473.5A.
Stevens PA, Pettenazzo A, Brasch F, Mulugeta S, Baritussio A, Ochs M, et al. 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.
Stevens, Paul A., et al. “Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene.Pediatr Res, vol. 57, no. 1, Jan. 2005, pp. 89–98. Pubmed, doi:10.1203/01.PDR.0000147567.02473.5A.
Stevens PA, Pettenazzo A, Brasch F, Mulugeta S, Baritussio A, Ochs M, Morrison L, Russo SJ, Beers MF. 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.

Published In

Pediatr Res

DOI

ISSN

0031-3998

Publication Date

January 2005

Volume

57

Issue

1

Start / End Page

89 / 98

Location

United States

Related Subject Headings

  • Transfection
  • Tomography, X-Ray Computed
  • Time Factors
  • Surface-Active Agents
  • Recombinant Fusion Proteins
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Alveolar Proteinosis
  • Protein Transport
  • Phospholipids
  • Pediatrics