PT - JOURNAL ARTICLE AU - Marie Legendre AU - Afifaa Butt AU - Raphaël Borie AU - Marie-Pierre Debray AU - Diane Bouvry AU - Emilie Filhol-Blin AU - Tifenn Desroziers AU - Valérie Nau AU - Bruno Copin AU - Florence Dastot-Le Moal AU - Mélanie Héry AU - Philippe Duquesnoy AU - Nathalie Allou AU - Anne Bergeron AU - Julien Bermudez AU - Aurélie Cazes AU - Anne-Laure Chene AU - Vincent Cottin AU - Bruno Crestani AU - Jean-Charles Dalphin AU - Christine Dombret AU - Bérénice Doray AU - Clairelyne Dupin AU - Violaine Giraud AU - Anne Gondouin AU - Laurent Gouya AU - Dominique Israël-Biet AU - Caroline Kannengiesser AU - Aurélie Le Borgne AU - Sylvie Leroy AU - Elisabeth Longchampt AU - Gwenaël Lorillon AU - Hilario Nunes AU - Clément Picard AU - Martine Reynaud-Gaubert AU - Julie Traclet AU - Paul de Vuyst AU - Aurore Coulomb L'Hermine AU - Annick Clement AU - Serge Amselem AU - Nadia Nathan TI - Functional assessment and phenotypic heterogeneity of <em>SFTPA1</em> and <em>SFTPA2</em> mutations in interstitial lung diseases and lung cancer AID - 10.1183/13993003.02806-2020 DP - 2020 Dec 01 TA - European Respiratory Journal PG - 2002806 VI - 56 IP - 6 4099 - http://erj.ersjournals.com/content/56/6/2002806.short 4100 - http://erj.ersjournals.com/content/56/6/2002806.full SO - Eur Respir J2020 Dec 01; 56 AB - Introduction Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five 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 or SFTPA2 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 in 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 six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.Discussion This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.SFTPA1 and SFTPA2 mutations lead to similar alterations in SP-A secretion and lung tissue expression. They are associated with a highly variable phenotypic expression ranging from incomplete penetrance to severe interstitial lung diseases and lung cancer. https://bit.ly/30SrEVb