Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency

Brasch, Frank; Schimanski, Sven; Mühlfeld, Christian; Barlage, Stefan; Langmann, Thomas; Aslanidis, Charalampos; Boettcher, Alfred; Dada, Ashraf; Schroten, Horst; Mildenberger, Eva; Prueter, Eric; Ballmann, Manfred; Ochs, Matthias; Johnen, Georg; Griese, Matthias; 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. 571-80. New York, N.Y.: American Lung Association 10.1164/rccm.200509-1535OC

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RATIONALE: 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. 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:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Mühlfeld, Christian and Ochs, Matthias

ISSN:

1073-449X

ISBN:

16728712

Publisher:

American Lung Association

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:46

Last Modified:

04 May 2014 23:13

Publisher DOI:

10.1164/rccm.200509-1535OC

PubMed ID:

16728712

Web of Science ID:

000240254800016

URI:

https://boris.unibe.ch/id/eprint/18958 (FactScience: 1233)

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