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Published ahead of print on May 25, 2006, doi:10.1164/rccm.200509-1535OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 5, September 2006, 571-580

A more recent version of this article appeared on September 1, 2006
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Submitted on September 30, 2005
Accepted on May 19, 2006

Alteration of the Pulmonary Surfactant System in Full-term Infants with Hereditary ABCA3 Deficiency

Frank Brasch1, Sven Schimanski2, Christian Muehlfeld3, Stefan Barlage2, Thomas Langmann2, Charalampos Aslanidis2, Alfred Boettcher2, Ashraf Dada2, Horst Schroten4, Eva Mildenberger5, Eric Prueter6, Manfred Ballmann7, Matthias Ochs8, Georg Johnen9, Matthias Griese10, and Gerd Schmitz2*

1 Institute of Pathology, University of Bochum, Bochum, Germany; Division of Electron Microscopy, Department of Anatomy, University of Gottingen, Gottingen, Germany, 2 Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany, 3 Division of Electron Microscopy, Department of Anatomy, University of Gottingen, Gottingen, Germany, 4 Department of General Pediatrics, University of Dusseldorf, Dusseldorf, Germany, 5 Department of Pediatrics, Charite, Campus Benjamin Franklin and Klinikum Neukolln, Berlin, Germany, 6 Department of Pediatrics, Bethesda Hospital, Wuppertal, Germany, 7 Department of Pediatrics, Hannover Medical School, Hannover, Germany, 8 Institute of Anatomy, Experimental Morphology Unit, University of Bern, Bern, Switzerland, 9 Institute of Occupational Medicine (BGFA), University of Bochum, Bochum, Germany, 10 Pediatric Pneumology, Childrens' Hospital of the Ludwig-Maximilians-University, Munich, Germany

* To whom correspondence should be addressed. E-mail: gerd.schmitz{at}klinik.uni-regensburg.de.

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 ten out 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 (proSP-B), but only low levels and aggregates of mature surfactant protein B (SPB) within electron-dense bodies in type-II-pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of surfactant protein C (proSP-C) and cathepsin D. Surfactant protein A (SP-A) was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and proSP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and surfactant protein C (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.
Key words: ABCA3, surfactant, cathepsin D, immunohistochemistry, immunoelectron microscopy




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