Functional assessment of newly identified SFTPA1 and SFTPA2 mutations in patients with idiopathic interstitial pneumonia (IIP) and lung cancer

Abstract

Background: Heterozygous mutations in the SFTPA1 and SFTPA2 genes, encoding the surfactant protein SP-A1 and SP-A2 have been associated with rare forms of familial IIP and lung adenocarcinoma. We previously described 11 new heterozygous SFTPA1 and SFTPA2 variations in 13 unrelated patients including one newborn. The study aims to analyze the pathogenicity of those variations. Methods: We first analyzed the intrafamilial segregation of the identified variations with IIP and lung cancer. The production and the secretion of the mutant proteins were subsequently studied in HEK293T cells transiently expressing the SP-A proteins carrying the variations. Finally, SP-A expression was assessed on lung tissues of the patients. Results: In the studied families (38 adults, 3 children), the variations segregated with either IIP and/or lung cancer (37%) with an incomplete penetrance of the disease phenotype. The mean age at onset of the IIP was 45 years (0-68). Nine of the variations were located in the highly conserved carbohydrate recognition domain of the protein. In vitro, the mutant proteins were produced but their secretion was absent (n=9) or altered (n=2). The lung expression of SP-A studied in 3 unrelated patients showed an increased expression of SP-A in the cytoplasm of hypertrophic type 2 alveolar cells. Discussion and conclusion: The 11 identified SFTPA1 and SFTPA2 variations are pathogenic. They are associated with IIP and with an increased risk of lung cancer. They were identified mainly in adults but also in children. The pathophysiological consequences of their abnormal secretion/expression remain to be elucidated.