Brasch, Frank and Schimanski, Sven and Muehlfeld, Christian and Barlage, Stefan and Langmann, Thomas and Aslanidis, Charalampos and Boettcher, Alfred and Dada, Ashraf and Schroten, Horst and Mildenberger, Eva and Prueter, Eric and Ballmann, Manfred and Ochs, Matthias and Johnen, Georg and Griese, Matthias and Schmitz, Gerd (2006) Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 174 (5). pp. 571-580. ISSN 1073-449X,
Full text not available from this repository. (Request a copy)Abstract
Rationale: ABCA3 mutations are known to cause fatal surfactant deficiency. Objective: We studied ABCA3 protein expression in full-term new-borns 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. Conclusion: 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INTERSTITIAL LUNG-DISEASE; PROTEIN-B; ALVEOLAR PROTEINOSIS; II PNEUMOCYTES; TRANSPORTER SUPERFAMILY; RESPIRATORY-DISTRESS; MEMBRANE-PROTEIN; LAMELLAR BODIES; GENE; MUTATIONS; ABCA3; cathepsin D; immunoelectron microscopy; immunohistochemistry; surfactant |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2021 10:08 |
| Last Modified: | 01 Feb 2021 10:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/34045 |
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