Marie Legendre1,2,3, Afifaa Butt1,3, Raphaël Borie4, Marie-Pierre Debray5, Diane Bouvry6, Emilie Filhol-Blin2, Tifenn Desroziers1, Valérie Nau2, Bruno Copin2, Florence Dastot-Le Moal2, Mélanie Héry1, Philippe Duquesnoy1, Nathalie Allou7, Anne Bergeron8, Julien Bermudez9, Aurélie Cazes10, Anne-Laure Chene11, Vincent Cottin12, Bruno Crestani5, Jean-Charles Dalphin13, Christine Dombret5, Bérénice Doray14, Clairelyne Dupin8, Violaine Giraud15, Anne Gondouin13, Laurent Gouya8, Dominique Israël-Biet16, Caroline Kannengiesser17, Aurélie Le Borgne18, Sylvie Leroy19, Elisabeth Longchampt20, Gwenaël Lorillon8, Hilario Nunes6, Clément Picard21, Martine Reynaud-Gaubert9, Julie Traclet12, Paul de Vuyst22, Aurore Coulomb L'Hermine23, Annick Clement1,24, Serge Amselem1,2,3, Nadia Nathan1,24,3. 1. Sorbonne Université, Inserm Childhood Genetic Disorders, Armand Trousseau Hospital, Paris, France. 2. Dept of Genetics, Armand Trousseau Hospital, Sorbonne University, Assistance Publique Hôpitaux de Paris (APHP), Paris, France. 3. Both authors contributed equally. 4. Pulmonology Dept A, Bichat Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France. 5. Radiology Dept, Bichat Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France. 6. Pulmonology Dept, EA 2363, Avicenne Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris 13 University, COMUE Sorbonne Paris Cité, Bobigny, France. 7. Pulmonology Dept, Felix Guyon Hospital, Saint Denis de La Reunion, France. 8. Pulmonology Dept, Saint Louis Hospital, Université de Paris, Paris, France. 9. Pulmonology Dept and Lung Transplant Team, North Hospital - Assistance Publique Hôpitaux de Marseille (APHM), Marseille - MEPHI, IHU Méditerranée Infection, Aix-Marseille University, Marseille, France. 10. Pathology Dept, Bichat Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France. 11. Pulmonology Dept, University Hospital, Nantes, France. 12. Pulmonology Dept and Coordinating Reference Center for Rare Pulmonary Diseases OrphaLung, Hospices Civils de Lyon, Claude Bernard University Lyon 1, Lyon, France. 13. Pulmonology Dept, UMR-CNRS Chrono-Environnement 6249, CNRS and CHU, Besançon, France. 14. Genetic Dept, Felix Guyon Hospital, Saint Denis de La Reunion, France. 15. Pulmonology Dept, Ambroise Paré Hospital, Assistance Publique Hôpitaux de Paris (APHP), Boulogne Billancourt, France. 16. Pulmonology Dept, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France. 17. Genetic Dept, Bichat Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France. 18. Pulmonology Dept, Larrey Hospital, Toulouse, France. 19. Pulmonology Dept, Pasteur Hospital, Nice, France. 20. Pathology Dept, Foch Hospital, Suresnes, France. 21. Pulmonology Dept, Foch Hospital, Suresnes, France. 22. Pulmonology Dept, Erasme Hospital, Brussels, Belgium. 23. Pathology Dept, Armand Trousseau Hospital, Paris, France. 24. Pediatric Pulmonology Dept and Reference Center for Rare Lung Diseases RespiRare, Armand Trousseau Hospital, Paris, France.
Abstract
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.
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.
Authors: Francesco Amati; Anna Stainer; Marco Mantero; Andrea Gramegna; Edoardo Simonetta; Giulia Suigo; Antonio Voza; Anoop M Nambiar; Umberto Cariboni; Justin Oldham; Philip L Molyneaux; Paolo Spagnolo; Francesco Blasi; Stefano Aliberti Journal: Int J Mol Sci Date: 2022-01-17 Impact factor: 5.923