Background Pulmonary surfactant forms a lipid-rich monolayerthat coats the airways of the lung and is essential for properinflation and function of the lung. Surfactant is produced byalveolar type II cells, stored intracellularly in organellesknown as lamellar bodies, and secreted by exocytosis. The genefor ATP-binding cassette transporter A3 (ABCA3) is expressedin alveolar type II cells, and the protein is localized to lamellarbodies, suggesting that it has an important role in surfactantmetabolism.
Methods We sequenced each of the coding exons of the ABCA3 genein blood DNA from 21 racially and ethnically diverse infantswith severe neonatal surfactant deficiency for which the etiologicprocess was unknown. Lung tissue from four patients was examinedby high-resolution light and electron microscopy.
Results Nonsense and frameshift mutations, as well as mutationsin highly conserved residues and in splice sites of the ABCA3gene were identified in 16 of the 21 patients (76 percent).In five consanguineous families with mutations, each pair ofsiblings was homozygous for the same mutation and each mutationwas found in only one family. Markedly abnormal lamellar bodieswere observed by ultrastructural examination of lung tissuefrom four patients with different ABCA3 mutations, includingnonsense, splice-site, and missense mutations.
Conclusions Mutation of the ABCA3 gene causes fatal surfactantdeficiency in newborns. ABCA3 is critical for the proper formationof lamellar bodies and surfactant function and may also be importantfor lung function in other pulmonary diseases. Since it is closelyrelated to ABCA1 and ABCA4, proteins that transport phospholipidsin macrophages and photoreceptor cells, it may have a role insurfactant phospholipid metabolism.
Source Information
From the Human Genetics Section, Laboratory of Genomic Diversity, National Cancer Institute — Frederick, Frederick, Md. (S.S., T.A., M.D.); the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore (L.M.N.); and Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (S.E.W., J.A.W.).
Address reprint requests to Dr. Dean at Bldg. 560, Rm. 21-18, NCI — Frederick, Frederick, MD 21702, or at dean{at}ncifcrf.gov.
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