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 <strong><em>SFTPA1</em></strong> and <strong><em>SFTPA2</em></strong> mutations in interstitial lung diseases and lung cancer AID - 10.1183/13993003.02806-2020 DP - 2020 Jan 01 TA - European Respiratory Journal PG - 2002806 4099 - http://erj.ersjournals.com/content/early/2020/07/23/13993003.02806-2020.short 4100 - http://erj.ersjournals.com/content/early/2020/07/23/13993003.02806-2020.full AB - 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Legendre has nothing to disclose.Conflict of interest: Dr. Butt has nothing to disclose.Conflict of interest: Dr. Borie reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Roche, personal fees from Savapharma, outside the submitted work;.Conflict of interest: Dr. Debray has nothing to disclose.Conflict of interest: Dr. Bouvry has nothing to disclose.Conflict of interest: Dr. Filhol-Blin has nothing to disclose.Conflict of interest: Dr. Desroziers has nothing to disclose.Conflict of interest: Dr. Nau has nothing to disclose.Conflict of interest: Dr. Copin has nothing to disclose.Conflict of interest: Dr. Dastot Le Moal has nothing to disclose.Conflict of interest: Dr. Héry has nothing to disclose.Conflict of interest: Dr. Duquesnoy has nothing to disclose.Conflict of interest: Dr. Allou has nothing to disclose.Conflict of interest: Dr. Bergeron has nothing to disclose.Conflict of interest: Dr. Bermudez has nothing to disclose.Conflict of interest: Dr. Cazes reports other from Boehringer Ingelheim, Roche, outside the submitted work;.Conflict of interest: Dr. Chene has nothing to disclose.Conflict of interest: Dr. Cottin reports personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Bayer / MSD, personal fees from Novartis, personal fees and non-financial support from Roche / Promedior, personal fees from Sanofi, personal fees from Celgene, personal fees from Galapagos, personal fees from Galecto, personal fees from Shionogi, personal fees from Astra Zeneca, outside the submitted work;.Conflict of interest: Dr. Crestani has nothing to disclose.Conflict of interest: Dr. Dalphin has nothing to disclose.Conflict of interest: Dr. Dombret has nothing to disclose.Conflict of interest: Dr. Doray has nothing to disclose.Conflict of interest: Dr. Dupin reports personal fees, non-financial support and other from Astra-Zeneca, personal fees, non-financial support and other from Boehringer, personal fees, non-financial support and other from GSK, personal fees and other from Chiesi, personal fees and non-financial support from Sanofi, personal fees, non-financial support and other from Novartis, non-financial support and other from Roche, outside the submitted work;.Conflict of interest: Dr. Giraud has nothing to disclose.Conflict of interest: Dr. Gondouin has nothing to disclose.Conflict of interest: Dr. Gouya has nothing to disclose.Conflict of interest: Dr. Israël-Biet has nothing to disclose.Conflict of interest: Dr. Kannengiesser has nothing to disclose.Conflict of interest: Dr. Le Borgne has nothing to disclose.Conflict of interest: Dr. Leroy has nothing to disclose.Conflict of interest: Dr. Longchampt has nothing to disclose.Conflict of interest: Dr. Lorillon has nothing to disclose.Conflict of interest: Dr. Nunes has nothing to disclose.Conflict of interest: Dr. Picard has nothing to disclose.Conflict of interest: Dr. Reynaud-Gaubert has nothing to disclose.Conflict of interest: Dr. Traclet has nothing to disclose.Conflict of interest: Dr. de Vuyst has nothing to disclose.Conflict of interest: Dr. Coulomb L'Hermine has nothing to disclose.Conflict of interest: Dr. Clement has nothing to disclose.Conflict of interest: Dr. Amselem has nothing to disclose.Conflict of interest: Dr. Nathan reports grants from Société de pneumologie pédiatrique et d'allergologie (France), outside the submitted work.