title: Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency.
abstract: BACKGROUND
  ABCA3 mutations are known to cause fatal surfactant deficiency.
  
  
  OBJECTIVE
  We studied ABCA3 protein expression in full-term newborns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis.
  
  
  METHODS
  Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting.
  
  
  RESULTS
  ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively.
  
  
  CONCLUSIONS
  Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.
authors.affiliation: Institute of Pathology, University of Bochum, Bochum.
authors.forename: Frank
authors.initials: F
authors.lastname: Brasch
authors.forename: Sven
authors.initials: S
authors.lastname: Schimanski
authors.forename: Christian
authors.initials: C
authors.lastname: Mühlfeld
authors.forename: Stefan
authors.initials: S
authors.lastname: Barlage
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.forename: Charalampos
authors.initials: C
authors.lastname: Aslanidis
authors.forename: Alfred
authors.initials: A
authors.lastname: Boettcher
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dada
authors.forename: Horst
authors.initials: H
authors.lastname: Schroten
authors.forename: Eva
authors.initials: E
authors.lastname: Mildenberger
authors.forename: Eric
authors.initials: E
authors.lastname: Prueter
authors.forename: Manfred
authors.initials: M
authors.lastname: Ballmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.forename: Georg
authors.initials: G
authors.lastname: Johnen
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D018893:Bronchoalveolar Lavage; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism*; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D047929:Term Birth
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037661:Pulmonary Surfactant-Associated Proteins