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.
Yanagi, T., Akiyama, M., Nishihara, H., Sakai, K., Nishie, W., Tanaka, S., Shimizu, H.
(2008). Harlequin ichthyosis model mouse reveals alveolar collapse and severe fetal skin barrier defects. Hum Mol Genet
17: 3075-3083
[Abstract][Full Text]
Gower, W. A., Wert, S. E., Nogee, L. M.
(2008). Inherited Surfactant Disorders. NeoReviews
9: e458-e467
[Abstract][Full Text]
Faro, A., Hamvas, A.
(2008). Lung Transplantation for Inherited Disorders of Surfactant Metabolism. NeoReviews
9: e468-e476
[Abstract][Full Text]
Matsumura, Y., Ban, N., Inagaki, N.
(2008). Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol.
295: L698-L707
[Abstract][Full Text]
Abdel-Latif, M E, Oei, J, Ward, M, Wills, E J, Tobias, V, Lui, K
(2008). Galvanised by a respiratory distress diagnosis. EDUCATION AND PRACTICE
93: 112-119
[Full Text]
Wan, H., Luo, F., Wert, S. E., Zhang, L., Xu, Y., Ikegami, M., Maeda, Y., Bell, S. M., Whitsett, J. A.
(2008). Kruppel-like factor 5 is required for perinatal lung morphogenesis and function. Development
135: 2563-2572
[Abstract][Full Text]
Young, L. R., Nogee, L. M., Barnett, B., Panos, R. J., Colby, T. V., Deutsch, G. H.
(2008). Usual Interstitial Pneumonia in an Adolescent With ABCA3 Mutations. Chest
134: 192-195
[Abstract][Full Text]
Ikegami, M., Falcone, A., Whitsett, J. A.
(2008). STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury. J. Appl. Physiol.
104: 1753-1760
[Abstract][Full Text]
Matsuzaki, Y., Besnard, V., Clark, J. C., Xu, Y., Wert, S. E., Ikegami, M., Whitsett, J. A.
(2008). STAT3 Regulates ABCA3 Expression and Influences Lamellar Body Formation in Alveolar Type II Cells. Am. J. Respir. Cell Mol. Bio.
38: 551-558
[Abstract][Full Text]
Whitsett, J. A
(2008). Hereditary disorders of surfactant homeostasis cause acute and chronic lung disease in infancy. Thorax
63: 295-296
[Full Text]
Inoue, Y., Trapnell, B. C., Tazawa, R., Arai, T., Takada, T., Hizawa, N., Kasahara, Y., Tatsumi, K., Hojo, M., Ichiwata, T., Tanaka, N., Yamaguchi, E., Eda, R., Oishi, K., Tsuchihashi, Y., Kaneko, C., Nukiwa, T., Sakatani, M., Krischer, J. P., Nakata, K., for the Japanese Center of the Rare Lung Diseases,
(2008). Characteristics of a Large Cohort of Patients with Autoimmune Pulmonary Alveolar Proteinosis in Japan. Am. J. Respir. Crit. Care Med.
177: 752-762
[Abstract][Full Text]
Doan, M L, Guillerman, R P, Dishop, M K, Nogee, L M, Langston, C, Mallory, G B, Sockrider, M M, Fan, L L
(2008). Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax
63: 366-373
[Abstract][Full Text]
Wojcik, A. J., Skaflen, M. D., Srinivasan, S., Hedrick, C. C.
(2008). A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis. J. Immunol.
180: 4273-4282
[Abstract][Full Text]
Baldan, A., Gomes, A. V., Ping, P., Edwards, P. A.
(2008). Loss of ABCG1 Results in Chronic Pulmonary Inflammation. J. Immunol.
180: 3560-3568
[Abstract][Full Text]
Burke, M. A., Mutharasan, R. K., Ardehali, H.
(2008). The Sulfonylurea Receptor, an Atypical ATP-Binding Cassette Protein, and Its Regulation of the KATP Channel. Circ. Res.
102: 164-176
[Abstract][Full Text]
Deutsch, G. H., Young, L. R., Deterding, R. R., Fan, L. L., Dell, S. D., Bean, J. A., Brody, A. S., Nogee, L. M., Trapnell, B. C., Langston, C., and the Pathology Cooperative Group:, , Albright, E. A., Askin, F. B., Baker, P., Chou, P. M., Cool, C. M., Coventry, S. C., Cutz, E., Davis, M. M., Dishop, M. K., Galambos, C., Patterson, K., Travis, W. D., Wert, S. E., White, F. V., on behalf of the ChILD Research Co-operative,
(2007). Diffuse Lung Disease in Young Children: Application of a Novel Classification Scheme. Am. J. Respir. Crit. Care Med.
176: 1120-1128
[Abstract][Full Text]
Besnard, V., Xu, Y., Whitsett, J. A.
(2007). Sterol response element binding protein and thyroid transcription factor-1 (Nkx2.1) regulate Abca3 gene expression. Am. J. Physiol. Lung Cell. Mol. Physiol.
293: L1395-L1405
[Abstract][Full Text]
Cheong, N., Zhang, H., Madesh, M., Zhao, M., Yu, K., Dodia, C., Fisher, A. B., Savani, R. C., Shuman, H.
(2007). ABCA3 Is Critical for Lamellar Body Biogenesis in Vivo. J. Biol. Chem.
282: 23811-23817
[Abstract][Full Text]
Andreeva, A. V., Kutuzov, M. A., Voyno-Yasenetskaya, T. A.
(2007). Regulation of surfactant secretion in alveolar type II cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
293: L259-L271
[Abstract][Full Text]
Sakai, H., Tanaka, Y., Tanaka, M., Ban, N., Yamada, K., Matsumura, Y., Watanabe, D., Sasaki, M., Kita, T., Inagaki, N.
(2007). ABCA2 Deficiency Results in Abnormal Sphingolipid Metabolism in Mouse Brain. J. Biol. Chem.
282: 19692-19699
[Abstract][Full Text]
Thomas, H., Risma, K. A., Graham, T. B., Brody, A. S., Deutsch, G. H., Young, L. R., Joseph, P. M.
(2007). A Kindred of Children With Interstitial Lung Disease. Chest
132: 221-230
[Abstract][Full Text]
Young, L. R., Pasula, R., Gulleman, P. M., Deutsch, G. H., McCormack, F. X.
(2007). Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis. Am. J. Respir. Cell Mol. Bio.
37: 67-74
[Abstract][Full Text]
Yamanaka, Y., Akiyama, M., Sugiyama-Nakagiri, Y., Sakai, K., Goto, M., McMillan, J. R., Ota, M., Sawamura, D., Shimizu, H.
(2007). Expression of the Keratinocyte Lipid Transporter ABCA12 in Developing and Reconstituted Human Epidermis. Am. J. Pathol.
171: 43-52
[Abstract][Full Text]
Ban, N., Matsumura, Y., Sakai, H., Takanezawa, Y., Sasaki, M., Arai, H., Inagaki, N.
(2007). ABCA3 as a Lipid Transporter in Pulmonary Surfactant Biogenesis. J. Biol. Chem.
282: 9628-9634
[Abstract][Full Text]
Fitzgerald, M. L., Xavier, R., Haley, K. J., Welti, R., Goss, J. L., Brown, C. E., Zhuang, D. Z., Bell, S. A., Lu, N., Mckee, M., Seed, B., Freeman, M. W.
(2007). ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J. Lipid Res.
48: 621-632
[Abstract][Full Text]
Schroeder, L. K., Kremer, S., Kramer, M. J., Currie, E., Kwan, E., Watts, J. L., Lawrenson, A. L., Hermann, G. J.
(2007). Function of the Caenorhabditis elegans ABC Transporter PGP-2 in the Biogenesis of a Lysosome-related Fat Storage Organelle. Mol. Biol. Cell
18: 995-1008
[Abstract][Full Text]
Boyer, D., Westra, S. J., Kinane, T. B., Stone, J. R.
(2007). Case 3-2007 -- A 3-Year-Old Boy with Recurrent Episodes of Respiratory Insufficiency. NEJM
356: 398-407
[Full Text]
Daleke, D. L.
(2007). Phospholipid Flippases. J. Biol. Chem.
282: 821-825
[Full Text]
Stahlman, M. T., Besnard, V., Wert, S. E., Weaver, T. E., Dingle, S., Xu, Y., von Zychlin, K., Olson, S. J., Whitsett, J. A.
(2007). Expression of ABCA3 in Developing Lung and Other Tissues. J. Histochem. Cytochem.
55: 71-83
[Abstract][Full Text]
Markart, P., Ruppert, C., Wygrecka, M., Schmidt, R., Korfei, M., Harbach, H., Theruvath, I., Pison, U., Seeger, W., Guenther, A., Witt, H.
(2007). Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias. Eur Respir J
29: 134-137
[Abstract][Full Text]
Ohtsuki, M., Taketomi, Y., Arata, S., Masuda, S., Ishikawa, Y., Ishii, T., Takanezawa, Y., Aoki, J., Arai, H., Yamamoto, K., Kudo, I., Murakami, M.
(2006). Transgenic Expression of Group V, but Not Group X, Secreted Phospholipase A2 in Mice Leads to Neonatal Lethality because of Lung Dysfunction. J. Biol. Chem.
281: 36420-36433
[Abstract][Full Text]
Matsumura, Y., Ban, N., Ueda, K., Inagaki, N.
(2006). Characterization and Classification of ATP-binding Cassette Transporter ABCA3 Mutants in Fatal Surfactant Deficiency. J. Biol. Chem.
281: 34503-34514
[Abstract][Full Text]
Baldan, A., Tarr, P., Vales, C. S., Frank, J., Shimotake, T. K., Hawgood, S., Edwards, P. A.
(2006). Deletion of the Transmembrane Transporter ABCG1 Results in Progressive Pulmonary Lipidosis. J. Biol. Chem.
281: 29401-29410
[Abstract][Full Text]
Brasch, F., Schimanski, S., Muhlfeld, C., Barlage, S., Langmann, T., Aslanidis, C., Boettcher, A., Dada, A., Schroten, H., Mildenberger, E., Prueter, E., Ballmann, M., Ochs, M., Johnen, G., Griese, M., Schmitz, G.
(2006). Alteration of the Pulmonary Surfactant System in Full-Term Infants with Hereditary ABCA3 Deficiency. Am. J. Respir. Crit. Care Med.
174: 571-580
[Abstract][Full Text]
Akiyama, M.
(2006). Pathomechanisms of Harlequin Ichthyosis and ABCA Transporters in Human Diseases.. Arch Dermatol
142: 914-918
[Abstract][Full Text]
Martinez, F. J., Keane, M. P.
(2006). Update in diffuse parenchymal lung diseases 2005.. Am. J. Respir. Crit. Care Med.
173: 1066-1071
[Full Text]
Bush, A.
(2006). Update in pediatrics 2005.. Am. J. Respir. Crit. Care Med.
173: 585-592
[Full Text]
Martis, P. C., Whitsett, J. A., Xu, Y., Perl, A.-K. T., Wan, H., Ikegami, M.
(2006). C/EBP{alpha} is required for lung maturation at birth. Development
133: 1155-1164
[Abstract][Full Text]
Lawson, W. E., Loyd, J. E.
(2006). The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease?. Proc Am Thorac Soc
3: 345-349
[Abstract][Full Text]
Fernandez-Valdivia, R., Zhang, Y., Pai, S., Metzker, M. L., Schumacher, A.
(2006). l7Rn6 Encodes a Novel Protein Required for Clara Cell Function in Mouse Lung Development. Genetics
172: 389-399
[Abstract][Full Text]
Deterding, R., Fan, L. L.
(2005). Surfactant Dysfunction Mutations in Children's Interstitial Lung Disease and Beyond. Am. J. Respir. Crit. Care Med.
172: 940-941
[Full Text]
Bullard, J. E., Wert, S. E., Whitsett, J. A., Dean, M., Nogee, L. M.
(2005). ABCA3 Mutations Associated with Pediatric Interstitial Lung Disease. Am. J. Respir. Crit. Care Med.
172: 1026-1031
[Abstract][Full Text]
Guttentag, S. H., Akhtar, A., Tao, J.-Q., Atochina, E., Rusiniak, M. E., Swank, R. T., Bates, S. R.
(2005). Defective Surfactant Secretion in a Mouse Model of Hermansky-Pudlak Syndrome. Am. J. Respir. Cell Mol. Bio.
33: 14-21
[Abstract][Full Text]
Lajoie, P., Guay, G., Dennis, J. W., Nabi, I. R.
(2005). The lipid composition of autophagic vacuoles regulates expression of multilamellar bodies. J. Cell Sci.
118: 1991-2003
[Abstract][Full Text]
Kim, W. S., Fitzgerald, M. L., Kang, K., Okuhira, K.-i., Bell, S. A., Manning, J. J., Koehn, S. L., Lu, N., Moore, K. J., Freeman, M. W.
(2005). Abca7 Null Mice Retain Normal Macrophage Phosphatidylcholine and Cholesterol Efflux Activity despite Alterations in Adipose Mass and Serum Cholesterol Levels. J. Biol. Chem.
280: 3989-3995
[Abstract][Full Text]
Raju, T. N.K., Ariagno, R. L., Higgins, R., Marter, L. J. V.
(2005). Research in Neonatology for the 21st Century: Executive Summary of the National Institute of Child Health and Human Development-American Academy of Pediatrics Workshop. Part I: Academic Issues. Pediatrics
115: 468-474
[Abstract][Full Text]
Latzin, P, Tredano, M, Wust, Y, de Blic, J, Nicolai, T, Bewig, B, Stanzel, F, Kohler, D, Bahuau, M, Griese, M
(2005). Anti-GM-CSF antibodies in paediatric pulmonary alveolar proteinosis. Thorax
60: 39-44
[Abstract][Full Text]
Wan, H., Xu, Y., Ikegami, M., Stahlman, M. T., Kaestner, K. H., Ang, S.-L., Whitsett, J. A.
(2004). Foxa2 is required for transition to air breathing at birth. Proc. Natl. Acad. Sci. USA
101: 14449-14454
[Abstract][Full Text]
Bush, A.
(2004). Paediatric interstitial lung disease: not just kid's stuff. Eur Respir J
24: 521-523
[Full Text]
Whitsett, J. A., Wert, S. E., Trapnell, B. C.
(2004). Genetic disorders influencing lung formation and function at birth. Hum Mol Genet
13: R207-R215
[Abstract][Full Text]
Zhou, J., You, Y., Ryan, A. J., Mallampalli, R. K.
(2004). Upregulation of surfactant synthesis triggers ABCA1-mediated basolateral phospholipid efflux. J. Lipid Res.
45: 1758-1767
[Abstract][Full Text]
(2004). Gene for Respiratory Distress Syndrome Identified. JWatch Women's Health
2004: 2-2
[Full Text]
Hallman, M.
(2004). Lung Surfactant, Respiratory Failure, and Genes. NEJM
350: 1278-1280
[Full Text]
Previous
