Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer

Hum Mol Genet. 2016 Apr 15;25(8):1457-67. doi: 10.1093/hmg/ddw014. Epub 2016 Jan 19.


Idiopathic interstitial pneumonias (IIPs) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality, which can occur at all ages. In adults, the most common form of IIPs, idiopathic pulmonary fibrosis (IPF), has been associated with an increased frequency of lung cancer. The molecular basis of IIPs remains unknown in most cases. This study investigates IIP pathophysiology in 12 families affected by IPF and lung cancer. We identified, in a multigenerational family, nine members carrying a heterozygous missense mutation with evidence of pathogenicity in SFTPA1 that encodes the surfactant protein (SP)-A1. The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-containing proteins. As shown through functional studies, the p.Trp211Arg mutation impairs SP-A1 secretion. Immunohistochemistry studies on patient alveolar epithelium showed an altered SP-A expression pattern. Overall, this first report of a germline molecular defect in SFTPA1 unveils the key role of SP-A1 in the occurrence of several chronic respiratory diseases, ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients. These data also clearly show that, in spite of their structural and functional similarities, SP-A1 and SP-A2 are not redundant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Idiopathic Interstitial Pneumonias / genetics*
  • Idiopathic Interstitial Pneumonias / pathology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Pulmonary Surfactant-Associated Protein A / genetics*
  • Pulmonary Surfactant-Associated Protein A / metabolism
  • Sequence Analysis, DNA


  • Pulmonary Surfactant-Associated Protein A
  • SFTPA1 protein, human