Published ahead of print on May 25, 2006, doi:10.1164/rccm.200509-1535OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200509-1535OC
Alteration of the Pulmonary Surfactant System in Full-Term Infants with Hereditary ABCA3 DeficiencyInstitute of Pathology, and Institute of Occupational Medicine (BGFA), University of Bochum, Bochum; Division of Electron Microscopy, Department of Anatomy, University of Göttingen, Göttingen; Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg; Department of General Pediatrics, University of Düsseldorf, Düsseldorf; Department of Pediatrics, Charité, Campus Benjamin Franklin, and Klinikum Neukölln, Berlin; Department of Pediatrics, Bethesda Hospital, Wuppertal; Department of Pediatrics, Hannover Medical School, Hannover; Pediatric Pneumology, Childrens' Hospital of the Ludwig-Maximilians-University, Munich, Germany; and Institute of Anatomy, Experimental Morphology Unit, University of Bern, Bern, Switzerland Correspondence and requests for reprints should be addressed to Prof. Dr. G. Schmitz, M.D., Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany. 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 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.
Key Words: ABCA3 • cathepsin D • immunoelectron microscopy • immunohistochemistry • surfactant This article has been cited by other articles:
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