ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells

{ "0" : "Department of Physiology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan" , "1" : "Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan" , "2" : "Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-Ku, Kawasaki 211-8533, Japan" , "3" : "Department of Pulmonary Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8375, Japan" , "4" : "Department of Pathology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan" , "5" : "Department of Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan" , "7" : "ATP-binding cassette transporter" , "8" : "Alveolar type II cell" , "9" : "Lipid transport" , "10" : "Surfactant" , "11" : "Lamellar body" , "12" : "Surfactant protein A" , "13" : "ABC, ATP-binding cassette" , "14" : "PCR, polymerase chain reaction" , "15" : "SP-A, surfactant protein A" , "16" : "PBS, phosphate-buffered saline" , "17" : "DAB, 3,3′-diaminobenzidine-4HCl"}
FEBS Letters (Impact Factor: 3.34). 12/2001; 508(2):221-225. DOI: 10.1016/S0014-5793(01)03056-3

ABSTRACT The ABCA3 gene, of the ABCA subclass of ATP-binding cassette (ABC) transporters, is expressed exclusively in lung. We report here the cloning, molecular characterization, and distribution of human ABCA3 in the lung. Immunoblot analysis using the specific antibody reveals a 150-kDa protein in the crude membrane fraction of human lung. Immunohistochemical analyses of alveoli show that ABCA3 is expressed only in the type II cells expressing surfactant protein A. At the ultrastructural level, ABCA3 immunoreactivity was detected mostly at the limiting membrane of the lamellar bodies. Since members of the ABCA transporter family are known to be involved in transmembrane transport of endogenous lipids, our findings suggest that ABCA3 plays an important role in the formation of pulmonary surfactant in type II cells.

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    ABSTRACT: Rationale: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease (chILD). Most ABCA3 mutations are private. Objective: To determine genotype-phenotype correlations for recessive ABCA3 mutations. Methods: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," while missense, predicted splice site mutations, and insertion/deletions were classified as "other". We compared age of presentation and outcomes for the three genotypes: null/null, other/other, and null/other. Measurements and Main Results: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared to 75% of infants with null/other or other/other genotypes (p=0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared to 62% of the null/other and other/other children (p<0.0001). Conclusions: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, while missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.
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