Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer

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.

Source: Human Molecular Genetics - March 22, 2016 Category: Genetics & Stem Cells Authors: Nathan, N., Giraud, V., Picard, C., Nunes, H., Dastot-Le Moal, F., Copin, B., Galeron, L., De Ligniville, A., Kuziner, N., Reynaud-Gaubert, M., Valeyre, D., Couderc, L.-J., Chinet, T., Borie, R., Crestani, B., Simansour, M., Nau, V., Tissier, S., Duquesno Tags: ARTICLES Source Type: research