Mutations in Surfactant Protein C and Interstitial Lung Disease

Abstract

Less than 5% of all cases of idiopathic interstitial lung disease (ILD) are due to familial pulmonary fibrosis. The clinical manifestations of familial pulmonary fibrosis are indistinguishable from the presenting symptoms in sporadic idiopathic pulmonary fibrosis. Mutations in SFTPC, the gene encoding surfactant protein C (SP-C), have been identified in kindreds with familial ILD as well as individuals with sporadic IPF. SP-C is a surfactant-associated protein that is essential for the reduction in surface tension at the air–liquid interface within the alveolus and the prevention of end-expiratory alveolar collapse. Because of its hydrophobic properties, SP-C is synthesized as a proprotein that is processed within the secretory pathway of alveolar type II cells as it is conducted to the lamellar body, the intracellular storage site of surfactant. The carboxy terminus of the proprotein appears to function as an intramolecular chaperone that guides posttranslational processing of the SP-C protein and the majority of mutations associated with ILD occur within this domain. Over 50 distinct SFTPC mutations have been identified and individuals with SP-C mutations range in age from infants to adults. The clinical manifestations extend from fatal respiratory failure to no clinically apparent respiratory symptoms. The pattern of inheritance appears to be autosomal dominant with variable penetrance. In infants and children, the most common histopathological pattern is nonspecific interstitial pneumonitis with features of pulmonary alveolar proteinosis. In contrast, usual interstitial pneumonitis is the most frequent pattern in adults. These mutations may cause lung fibrosis through protein misprocessing within the endoplasmic reticulum activating the unfolded protein response, proteasome dysfunction, and alveolar epithelial cell death. Alveolar type II cells expressing SP-C mutant proteins may be more susceptible to environmental factors that may trigger epithelial cell injury, death, and the development of parenchymal fibrosis. Understanding the pathogenetic mechanisms by which mutations in SP-C cause pulmonary fibrosis provides unique insights into the cellular and molecular pathogenesis of the idiopathic interstitial lung diseases.