Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease

Am J Med Genet A. 2004 Apr 1;126A(1):18-26. doi: 10.1002/ajmg.a.20670.


Pulmonary surfactant protein C (SP-C) is a highly hydrophobic peptide produced by type-II alveolar cells through the processing of a high-molecular weight precursor (pro-SP-C), that enhances surface tension and facilitates the recycling of pulmonary surfactant in vitro. Recently, two seemingly dominant-negative mutations of the pro-SP-C-encoding gene (SFTPC, MIM 178620), were reported in families with vertically-inherited interstitial lung disease (Nogee et al. [2001: N Engl J Med 344:573-579]; Thomas et al. [2002: Am J Respir Crit Care Med 165:1322-1328]). We have examined the SP-C protein and its precursor as well as the encoding gene, in a cohort of 34 sporadic or familial cases with unexplained respiratory distress (URD) in which surfactant protein B (SP-B) deficiency related to SFTPB mutation had been ruled out. One patient with complete SP-C deficiency had no detectable mutation of SFTPC. Of the 10 patients with abnormal pro-SP-C processing, as suggested from analysis of broncho-alveolar lavage (BAL) fluid, two distinct heterozygous SFTPC missense mutations were identified. The first, g.1286T > C (p.I73T), was de novo and resulted in progressive respiratory failure with intra-alveolar storage of a granular, protein- and lipid-rich, periodic acid Schiff (PAS)-positive material (pulmonary alveolar proteinosis (PAP)), and interstitial lung disease. The second, g.2125G > A (p.R167Q), was found in two PAP patients from the endogamous white settler population of Réunion Island in which URD has an unexpectedly high prevalence. Since this mutation was diagnosed in subjects from this subpopulation who did not have evidence for lung disease, we propose environmental exposures or modifier genes to play a role in the phenotype, as suggested from murine models lacking the SP-C protein, although we cannot rule out a rare polymorphism, hitherto restricted to that subpopulation. Most remarkably, these observations extend the phenotypic spectrum related to SFTPC mutation from interstitial lung disease to PAP. Notably, the reported mutations do not appear to be dominant negatives. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchoalveolar Lavage Fluid / chemistry
  • Child, Preschool
  • Cohort Studies
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Lung Diseases, Interstitial / genetics*
  • Lung Diseases, Interstitial / metabolism
  • Male
  • Mutation*
  • Pedigree
  • Peptides*
  • Phenotype
  • Pulmonary Alveolar Proteinosis / congenital*
  • Pulmonary Alveolar Proteinosis / diagnosis
  • Pulmonary Alveolar Proteinosis / genetics*
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Surfactant-Associated Protein C / analogs & derivatives*
  • Pulmonary Surfactant-Associated Protein C / genetics*
  • Pulmonary Surfactant-Associated Protein C / metabolism


  • Peptides
  • Pulmonary Surfactant-Associated Protein C
  • SFTPC protein, human

Associated data

  • OMIM/178620