title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
abstract: Idiopathic interstitial pneumonias (IIPs) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality, which can occur at all ages. In adults, the most common form of IIPs, idiopathic pulmonary fibrosis (IPF), has been associated with an increased frequency of lung cancer. The molecular basis of IIPs remains unknown in most cases. This study investigates IIP pathophysiology in 12 families affected by IPF and lung cancer. We identified, in a multigenerational family, nine members carrying a heterozygous missense mutation with evidence of pathogenicity in SFTPA1 that encodes the surfactant protein (SP)-A1. The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-containing proteins. As shown through functional studies, the p.Trp211Arg mutation impairs SP-A1 secretion. Immunohistochemistry studies on patient alveolar epithelium showed an altered SP-A expression pattern. Overall, this first report of a germline molecular defect in SFTPA1 unveils the key role of SP-A1 in the occurrence of several chronic respiratory diseases, ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients. These data also clearly show that, in spite of their structural and functional similarities, SP-A1 and SP-A2 are not redundant.
authors.affiliation: INSERM UMRS933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France, Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris 75012, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Nathan
authors.affiliation: Service de Pneumologie et Oncologie Thoracique, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne 92110, France.
authors.forename: Violaine
authors.initials: V
authors.lastname: Giraud
authors.affiliation: Service de Pneumologie, Hôpital Foch, Suresnes 92150, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Picard
authors.affiliation: Service de Pneumologie, Hôpital Avicenne, Assistance Publique Hôpitaux de Paris, Université Paris 13, COMUE Sorbonne Paris Cité, EA 2363, Bobigny 93000, France.
authors.forename: Hilario
authors.initials: H
authors.lastname: Nunes
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Dastot-Le Moal
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Copin
authors.affiliation: Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris 75012, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Galeron
authors.affiliation: Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris 75012, France.
authors.forename: Alice
authors.initials: A
authors.lastname: De Ligniville
authors.affiliation: Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris 75012, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kuziner
authors.affiliation: Service de Pneumologie et Transplantation Pulmonaire, CHU Nord Faculté de Médecine, URMITE- CNRS-UMR 6236, Aix Marseille Université, Marseille 13000, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Reynaud-Gaubert
authors.affiliation: Service de Pneumologie, Hôpital Avicenne, Assistance Publique Hôpitaux de Paris, Université Paris 13, COMUE Sorbonne Paris Cité, EA 2363, Bobigny 93000, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valeyre
authors.affiliation: Service de Pneumologie, Hôpital Foch, Suresnes 92150, France.
authors.forename: Louis-Jean
authors.initials: LJ
authors.lastname: Couderc
authors.affiliation: Service de Pneumologie et Oncologie Thoracique, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne 92110, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Chinet
authors.affiliation: Service de Pneumologie A, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Centre de Compétence des Maladies Pulmonaires Rares, Université Paris Diderot, Sorbonne Paris Cité, DHU FIRE, Paris 75018, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Borie
authors.affiliation: Service de Pneumologie A, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Centre de Compétence des Maladies Pulmonaires Rares, Université Paris Diderot, Sorbonne Paris Cité, DHU FIRE, Paris 75018, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: INSERM UMRS933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Simansour
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nau
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tissier
authors.affiliation: INSERM UMRS933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France.
authors.forename: Lamisse
authors.initials: L
authors.lastname: Mansour-Hendili
authors.affiliation: INSERM UMRS933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France, Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Legendre
authors.affiliation: Service de Génétique, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, Sorbonne Paris Cité, Paris 75018, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.affiliation: Service de Cytologie et Pathologie, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Sorbonne Universités, Paris 75012, France and.
authors.forename: Aurore
authors.initials: A
authors.lastname: Coulomb-L'Hermine
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique Hôpitaux de Paris, INSERM U1149, CNRS ERL 8252, Centre de Recherche sur L'inflammation, Laboratoire d'excellence, GR-Ex, Université Paris Diderot, Sorbonne Paris Cité, Colombes 92700, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: INSERM UMRS933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France, Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Paris 75012, France, serge.amselem@inserm.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.affiliation: INSERM UMRS933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France, Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique Hôpitaux de Paris, Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris 75012, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D037662:Pulmonary Surfactant-Associated Protein A; C445842:SFTPA1 protein, human