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

Abstract

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 http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.

Surfactant proteins in pediatric interstitial lung disease

“…In particular, no studies have compared the full range of these diseases, to yield better estimates of variability and to examine the relative importance of biochemical determinations of their BALF levels. It has been shown that the levels of SP-C in patients with known mutations in SFTPB (17,18), SFTPC (19,20), ABCA3 (21), and TTF1 (22) are low. Thus, we hypothesized that SP-C might serve as a helpful screening tool for such and additional surfactant dysfunction disorders.…”

Heterozygosity for ABCA3 Mutations Modifies the Severity of Lung Disease Associated with a Surfactant Protein C Gene (SFTPC) Mutation

“…Although surfactant phospholipids are primarily responsible for lowering surface tension, two small hydrophobic proteins, surfactant proteins B and C (SP-B and SP-C), have key roles in regulating surfactant function and metabolism (1). SP-C deficiency and mutations in the SP-C gene (SFTPC) have been associated with both sporadic interstitial lung disease (ILD) due to de novo mutations and familial ILD inherited as autosomal dominant (2)(3)(4)(5)(6)(7)(8)(9)(10). One particular SFTPC mutation, a substitution of threonine (T) for isoleucine (I) in codon 73 (I73T) has been identified in multiple unrelated families (9 -11).…”

Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation

“…3 In term infants, inherited mutations in the genes coding for surfactant protein-B, SFTPB (surfactant protein-B deficiency) and SFTPC have been identified as cause of respiratory failure. [4][5][6] Histopathology of surfactant protein-B deficiency resembles the adult form of alveolar proteinosis or a desquamative interstitial pneumonitis (DIP)-like pattern. 4,7 In addition to SFTPB and SFTPC mutations, inherited severe neonatal respiratory distress has recently been attributed to mutations in the ATPbinding cassette A3 transporter (ABCA3) gene.…”