title: Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations.
abstract: Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC - the gene encoding SP-C - SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.
authors.affiliation: Research core laboratories, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Peca
authors.affiliation: Division of Anatomopathology, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.affiliation: Department of Neurobiology, Care sciences and Society, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Johannson
authors.affiliation: Department of Pediatrics, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Shieh
authors.affiliation: Division of Anatomopathology, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Citti
authors.affiliation: Research core laboratories, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrini
authors.affiliation: Department of Pediatrics, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Salerno
authors.affiliation: Division of Pediatric Pulmonology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cazzato
authors.affiliation: Division of Pediatric intensive Care, Santobono Hospital, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Testa
authors.affiliation: Division of Neonatology, Villa Betania Hospital, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Messina
authors.affiliation: Division of Pediatric Intensive Care, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Onofri
authors.affiliation: Division of Clinical Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Westermark
authors.forename: Nicola
authors.initials: N
authors.lastname: Ullmann
authors.affiliation: Department of Pediatrics, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ullman
authors.affiliation: Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cogo
authors.affiliation: Department of Pediatrics, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Cutrera
authors.affiliation: 1] Department of Pediatrics, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA [2] Department of Medical and Surgical Neonatology, Bambino Gesu' Children's Hospital, Rome, Italy.
authors.forename: Olivier
authors.identifier: 0000000282083086
authors.initials: O
authors.lastname: Danhaive
mesh_terms: D000328:Adult; D001706:Biopsy; D002648:Child; D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000473:pathology / Q000648:ultrastructure*; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010641:Phenotype; D011486:Protein C / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics*
chemical_list: D011486:Protein C; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human