Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

Introduction Interstitial lung diseases (ILD) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein complex (SP)-A. Only 11 SFTPA1/2 mutations have so far been reported worldwide, of which 5 have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. Methods The consequences of the 11 SFTPA1/2 mutations were analysed both in vitro by studying the production and secretion of the corresponding mutated proteins and ex vivo by analysing SP-A expression on lung tissue samples. The associated disease phenotypes were documented. Results For the 11 identified mutations, protein production was preserved, but secretion was abolished. The expression pattern of lung SP-A, available in 6 patients, was altered. The family history reported ILD and/or lung adenocarcinoma in 13/14 (93%) families. Among the 28 SFTPA1/2 mutation carriers, the mean age at ILD onset was 45 [0.6–65] years and 48% of them underwent lung transplantation (mean age 51); 7 carriers were asymptomatic. Discussion This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that those pathogenic SFTPA1/A2 mutations share similar consequences on SP-A secretion in cell models and lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of the disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.