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ABCA3 Mutations Associated with Pediatric Interstitial Lung Disease

Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Human Genetics Section, Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland

Correspondence and requests for reprints should be addressed to Lawrence Nogee, M.D., Division of Neonatology, CMSC 6-104, 600 North Wolfe Street, Baltimore, MD 21287-3200. E-mail: lnogee{at}jhmi.edu

Rationale: ABCA3 is a member of the ATP-binding cassette family of proteins that mediate the translocation of a wide variety of substrates, including lipids, across cellular membranes. Mutations in the gene encoding ABCA3 were recently identified in full-term neonates with fatal surfactant deficiency.

Objective: To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease.

Methods: DNA samples were obtained from 195 children with chronic lung disease of unknown etiology. The 30 coding exons of the ABCA3 gene were sequenced in four unrelated children with a referring diagnosis of desquamative interstitial pneumonitis and who were older than 10 years at the time of enrollment.

Results: Three of four patients (ages 16, 23, and 11 years) with desquamative interstitial pneumonitis had ABCA3 mutations identified on both alleles. All three had the same missense mutation (E292V) and a second unique mutation. The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Immunohistochemical analysis of surfactant protein expression in three patients revealed a specific staining pattern for surfactant protein-B, which was the same pattern observed in several infants with fatal lung disease due to ABCA3 mutations.

Conclusion: ABCA3 mutations cause some types of interstitial lung disease in pediatric patients.

Key Words: desquamative interstitial pneumonitis • pulmonary alveolar proteinosis • surfactant

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