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      • Record: found
      • Abstract: found
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      Is Open Access

      Surfactant Protein C-associated interstitial lung disease; three different phenotypes of the same SFTPC mutation

      case-report

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          Abstract

          Background

          Monoallelic mutations of the Surfactant Protein C gene (SFTPC) are associated with Interstitial Lung Disease in children. I73T is the most common mutation, accounting for 30 % of all cases reported.

          Case presentation

          We describe three patients carrying the same I73T SPC mutation with very different phenotypes, clinical course (ranging from mild respiratory symptoms to death for respiratory failure) and outcome.

          Conclusions

          The disease mechanisms associated with SP-C mutations suggest that the combination of individual genetic background and environmental factors contribute largely to the wide variability of clinical expression. Infants, children and adults with ILD of unknown etiology should be investigated for SP-C genetic abnormalities.

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          High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C.

          Aaron Hamvas, Michael Landreh, Jenny Presto … (2012)
          BRICHOS domains are encoded in > 30 human genes, which are associated with cancer, neurodegeneration, and interstitial lung disease (ILD). The BRICHOS domain from lung surfactant protein C proprotein (proSP-C) is required for membrane insertion of SP-C and has anti-amyloid activity in vitro. Here, we report the 2.1 Å crystal structure of the human proSP-C BRICHOS domain, which, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry, reveals how BRICHOS domains may mediate chaperone activity. Observation of amyloid deposits composed of mature SP-C in lung tissue samples from ILD patients with mutations in the BRICHOS domain or in its peptide-binding linker region supports the in vivo relevance of the proposed mechanism. The results indicate that ILD mutations interfering with proSP-C BRICHOS activity cause amyloid disease secondary to intramolecular chaperone malfunction.
          Article 0 comments Cited 42 times – based on 0 reviews     Review now
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            Inhibition of cellular processing of surfactant protein C by drugs affecting intracellular pH gradients.

            Amanda M. Beers (1996)
            Surfactant protein C (SP-C) is a hydrophobic protein synthesized and secreted exclusively by alveolar type II cells through proteolysis of a 21-kDa propeptide (SP-C21) to produce the 3.7-kDa surface active form. Previous studies from this laboratory have demonstrated that early processing of proSP-C involves extensive intracellular proteolysis of the COOH terminus of proSP-C21 in subcellular compartments, which include the acidic type II cell-specific subcellular organelle, the lamellar body. (Beers, M. F., Kim, C. Y., Dodia, C., and Fisher, A. B.(1994) J. Biol. Chem. 269, 20318-20328). The role of intracellular pH gradients in SP-C processing was studied in freshly isolated rat type II cells. Using vital fluorescence microscopy, the pH indicator acridine orange (AO) identified intense fluorescence staining of acidic cytoplasmic vesicles within fresh type II cells. The AO vesicular staining pattern was similar in cells labeled with the lamellar body marker phosphine 3R and the phospholipid dye nile red. AO fluorescence was quenched by the addition of a membrane-permeable weak base, methylamine. Immunoprecipitation of cell lysates with anti-proSP-C antisera following pulse-chase labeling (0-2 h) with 35S-Translabel demonstrated rapid synthesis of 35S-proSP-C21 with a time-dependent appearance of 16- and 6-kDa intermediates (SP-C16 and SP-C6). Tricine polyacrylamide gel electrophoresis analysis of organic extracts of cell lysates showed time-dependent appearance of mature SP-C3.7. The addition of 5 mM methylamine significantly blocked the post-translational processing of proSP-C resulting in disruption of normal precursor-product relationships and inhibition of SP-C3.7 formation. Methylamine-treated cells exhibited slow accumulation of SP-C16 and SP-C6, a persistence of SP-C21, and an absence of SP-C3.7 for the duration of the chase period. The lysosomotropic agent chloroquine, the proton ionophore monensin, and bafilomycin A1, a specific vacuolar H+-ATPase inhibitor, each caused inhibition of proSP-C processing in a similar manner. These results demonstrate that normal post-translational proteolysis of proSP-C occurs in acidic intracellular compartments, which include the lamellar body, and that complete processing to SP-C3.7 is dependent upon maintenance of transmembrane pH gradients by a vacuolar H+-ATPase.
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              Author and article information

              Contributors
              Teresa Salerno: +39.06.68592020 , teresa.salerno@opbg.net
              Donatella Peca: donatella.peca@opbg.net
              Laura Menchini: laura.menchini@opbg.net
              Alessandra Schiavino: alessandra.schiavino@opbg.net
              Renata Boldrini: renata.boldrini@opbg.net
              Fulvio Esposito: ful.esp@virgilio.it
              Olivier Danhaive: Olivier.Danhaive@ucsf.edu
              Renato Cutrera: renato.cutrera@opbg.net
              Journal
              Journal ID (nlm-ta): Ital J Pediatr
              Journal ID (iso-abbrev): Ital J Pediatr
              Title: Italian Journal of Pediatrics
              Publisher: BioMed Central (London )
              ISSN (Electronic): 1824-7288
              Publication date (Electronic): 29 February 2016
              Publication date PMC-release: 29 February 2016
              Publication date Collection: 2016
              Volume: 42
              Electronic Location Identifier: 23
              Affiliations
              [ ]Pneumology Unit - Department of Pediatric Medicine, Bambino Gesù Children’s Hospital, IRCCS, Piazza S Onofrio 4, 00165 Rome, Italy
              [ ]Research Laboratory, Bambino Gesù Children’s Hospital, IRCCS, Piazza S Onofrio 4, 00165 Rome, Italy
              [ ]Department of Radiology, Bambino Gesù Children’s Hospital, IRCCS, Piazza S Onofrio 4, 00165 Rome, Italy
              [ ]Department of Pathology, Bambino Gesù Children’s Hospital, IRCCS, Piazza S Onofrio 4, 00165 Rome, Italy
              [ ]Pneumology Unit – Pediatric Hospital Santobono, Via Mario Fiore 6, 80123 Napoli, Italy
              [ ]Department of Pediatrics, University of California San Francisco, 101 Potrero Avenue, San Francisco, CA 94110 USA
              [ ]Department of Medical and Surgical Neonatology, Bambino Gesu’ Children’s Hospital, Piazza S.Onofrio 4, 00165 Rome, Italy
              Article
              Publisher ID: 235
              DOI: 10.1186/s13052-016-0235-x
              PMC ID: 4772310
              PubMed ID: 26925580
              SO-VID: 744042d0-c53d-4fc4-8f10-741ce9d8dea6
              Copyright © © Salerno et al. 2016
              License:

              Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

              History
              Date received : 9 September 2015
              Date accepted : 23 February 2016
              Categories
              Subject: Case Report
              Custom metadata
              issue-copyright-statement © The Author(s) 2016

              ScienceOpen disciplines: Pediatrics
              Keywords: surfactant protein c,sp-c surfactant protein c gene,children interstitial lung disease children
              Data availability:
              ScienceOpen disciplines: Pediatrics
              Keywords: surfactant protein c, sp-c surfactant protein c gene, children interstitial lung disease children

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